Ozempic, Vigovi, and similar drugs have become the darlings of the pharmaceutical industry in the 2020s. Studies are beginning to show that these drugs can help people lose weight more significantly than diet and exercise alone, and that their effects may extend far beyond that. But what exactly do these drugs do, and why do they seem to affect different aspects of our health?
The relationship between poor health and weight gain is more complicated than people often think, but obese people are at higher risk for health problems, and many people want to lose weight for understandable reasons, like being able to walk with less knee pain or sleep better without apnea. Unfortunately, as anyone who has tried to lose weight can tell you, it is very difficult to lose significant weight and keep it off long term.
This has changed dramatically with the arrival of drugs like Ozempic, but despite their effectiveness, there is still a lot of misunderstanding and mystery surrounding the mechanism of action of these drugs.
A powerful imitator
The active ingredient in Novo Nordisk’s Ozempic and Wegovi is semaglutide, which belongs to a group of drugs formally known as glucagon-like peptide-1 receptor agonists (GLP-1RA for short). GLP-1 is a hormone that plays a key role in regulating metabolism and hunger. It does this through several mechanisms.
For example, when we eat, our blood sugar levels begin to rise. In response, the intestine releases GLP-1, which stimulates the pancreas to produce insulin, which drives glucose from the blood into cells, lowering blood sugar levels. GLP-1 also interacts with the vagus nerve to slow the emptying of food from the stomach, promoting feelings of fullness while eating. Certain cells in the brain also produce GLP-1, and this GLP-1 in the brain is thought to suppress appetite and food cravings throughout the day.
When scientists first discovered GLP-1 in 1986 and found that it directly affected insulin production, they quickly began to suspect that GLP-1, or substances very similar to it, could be used to treat type 2 diabetes, a disease characterized by uncontrolled, chronically high blood sugar levels. But natural GLP-1 has a half-life of just a few minutes and doesn’t last long in the body. Eventually, scientists were able to develop a lab-made protein, GLP-1RA, that activates the same receptors as GLP-1, but lasts longer in the body.
The first GLP-1RA approved for type 2 diabetes was the drug exenatide, a synthetic version of a famous protein (exenin-4) first discovered in the sloshing venom of the Gila monster (Heloderma suspectum). Over the years, other GLP-1RAs have been developed, with semaglutide becoming the first approved diabetes drug, Ozempic, in 2017. But the basic principle of these drugs remains the same: to mimic and effectively enhance the natural function of GLP-1, according to Andrea Coviello, an endocrinologist and medical director of the University of North Carolina Medical Weight Program.
“When we made the synthetic version and started to improve it a little bit, we just extended the half-life,” Coviello told Gizmodo. Semaglutide in particular has a half-life of about a week, much longer than exenatide’s roughly 13 hours. One of semaglutide’s main improvements is that it prevents it from being rapidly broken down by the DPP-4 enzyme, and another allows it to bind tightly to the serum protein albumin, allowing it to remain in the blood longer without being filtered by the kidneys.
GLP-1RAs were originally developed to treat type 2 diabetes, but scientists have known since the early 1990s that GLP-1 could also be used to treat obesity because of its effects on hunger and fullness. The first GLP-1RA approved for the treatment of obesity was liraglutide, approved in 2014 under the name Saxenda, and a higher-dose version of semaglutide was approved in 2021 under the name Wegovy.
Benefits of GLP-1
While earlier GLP-1 drugs were extremely valuable to patients, the arrival of semaglutide really changed the landscape of obesity treatment. A large clinical trial showed that people taking Wegovy lost about 15% of their body weight over a year, far exceeding the typical success rate seen with diet and exercise alone and exceeding the typical success rate seen with traditional obesity medications. By comparison, people taking Saxenda in a similar trial lost about 7.5% of their body weight.
Some research suggests that obese people produce less natural GLP-1 in response to food, which may be the reason for their weight gain. It is tempting to think that these drugs simply fix the GLP-1 deficiency in obese people. However, this research is not conclusive, and obesity tends to be a complex condition with many different factors interacting. It may be more accurate to say that GLP-1RAs are one of the particularly powerful tools, if not the only one, that can be used to address the biological basis of obesity. That said, people taking these drugs generally feel a palpable sense of relief and report a dramatic reduction in “food noise,” or constant, intrusive thoughts about food.
Since the approval of Wegovi, it has become established that GLP-1RAs have benefits not only for obesity but also for many other health conditions. Large studies have found that semaglutide can reduce the risk of heart and kidney problems in obese people who are at high risk for those problems. Other studies have also found early evidence that GLP-1RAs may be able to reduce the risk of obesity-related cancer, depression, and even dementia. Many of these benefits appear to be related to the significant weight loss that comes with GLP-1 therapy. While obese people are not necessarily less healthy than the average person, obesity is associated with higher levels of inflammation, high blood pressure, and other bodily changes that may increase the risk of health problems such as type 2 diabetes and heart disease. So while weight loss may improve these factors, it alone does not explain all of the rosy benefits that may be associated with these drugs.
Some studies suggest that semaglutide may improve heart health even in people who lose little weight, due to its effects in reducing blood sugar and inflammation. Other studies have found preliminary data that semaglutide may reduce cravings for unhealthy habits such as heavy drinking and gambling, an unexpected phenomenon that may be related to the action of GLP-1 in the brain.
Ultimately, it appears that the effect of natural GLP-1 in regulating food intake comes primarily from brain-derived GLP-1, not from the gut. GLP-1 receptors in the brain also appear to play a role in regulating responses to addictive stimuli such as cocaine and other drugs through their interaction with dopamine, a neurotransmitter deeply involved in the reward system, although scientists are not yet sure about the exact mechanism. In any case, researchers are beginning larger trials of semaglutide, not only for alcoholism, but also for other brain-related diseases such as Alzheimer’s disease.
What’s wrong with GLP-1?
No drug is without risk, and GLP-1RAs are no exception. The most common side effects are gastrointestinal symptoms, such as nausea, vomiting, and constipation. According to Coviello, these too can be explained by the biology of GLP-1.
“So if you take these compounds for a few hours, they may have beneficial effects, like slowing down your gut movements a little bit, so you can digest food more efficiently,” she explained. “But if you extend the half-life to a day, or take them seven days a week, we think that slowing down your gut movements may contribute to feelings of fullness, nausea, and constipation in the long term, because your gut movements are a little slower.”
But more seriously, it’s believed that GLP-1 therapy can cause digestion to slow excessively, potentially resulting in a condition called gastroparesis. Gastroparesis is more flamboyantly known as gastroparesis, a term that refers to a degree of slowing of gastric emptying that is harmful to humans. Another serious side effect associated with the use of GLP-1RAs is intestinal obstruction or ileus. Last year, the FDA changed Ozempic’s labeling after reports of adverse events required it to mention the potential risk of ileus, but stopped short of confirming ileus as a side effect.
Thankfully, intestinal obstruction and gastroparesis appear to be rare complications of GLP-1RAs. No strong evidence has emerged so far regarding other potentially serious side effects, such as increased suicide risk or severe muscle loss, although it is certainly possible that scientists will discover new health risks that are not currently established. For now, GLP-1RAs appear to be safe and effective for the vast majority of patients who take them, and even the more unpleasant gastrointestinal side effects that GLP-1RAs cause tend to wane over time.
The future of obesity
Semaglutide and its brand name have come to symbolize a new era in obesity treatment, but this is just the beginning. Eli Lilly’s recently launched tirzepatide, for example, mimics both GLP-1 and another hunger-related hormone, GIP, and has already proven more effective than semaglutide. Novo Nordisk and other pharmaceutical companies are also developing their own successors, some of which combine GLP-1 with two other hunger-related hormones. Others are working to make these drugs easier to take, and one is studying whether a once-in-a-lifetime gene therapy could help cells naturally produce more GLP-1.
While all this research could be revolutionary, doctors like Coviello point out that these drugs don’t address the underlying causes that have made obesity such a big problem over time. The obesity rate among U.S. adults is currently about 42%, and the prevalence of obesity has continued to rise in many states since Wegobee was approved in 2021. Scientists will continue to study and improve these drugs, but they’re only part of a broader approach needed to address the growing public health problem.
“I think what we’ll see going forward will be even more sophisticated approaches than what we’re seeing today, and hopefully even better tolerated. But the big question that remains is why are we seeing this obesity epidemic? That question remains unanswered, despite significant advances in our understanding of the new mechanisms behind excessive weight gain,” she said. “If we can figure out what’s happened, what’s changed, and address that, the answer is to fix that, and we may not necessarily have to rely on better drugs that just mimic or enhance the natural signals in the body that have always been designed to address metabolism.”
Semaglutide and other GLP-1RAs are proving to be more useful than we had hoped, and the future looks bright for these drugs. But there are some health problems that no drug, no matter how miraculous it may seem, can cure on its own.
