Ozempic, Wegovy, and their cousins have become pharmaceutical darlings of the 2020s. These drugs help people lose more weight than diet and exercise alone, while research has begun to show that their benefits may extend even further. But what exactly makes them tick, and why do they seem to affect so many different aspects of our lives?
The link between poor health and overweight has been more complex than is often portrayed. But people living with obesity face a greater risk of certain health problems, and many people want to lose weight for understandable reasons, such as being able to walk with less knee pain or sleep soundly without apnea. Unfortunately, as most anyone who has tried to lose weight can tell you, it is very difficult to lose a lot of weight and keep it off for a long time.
The advent of Ozempic and others has changed that reality, but despite its success, there are still many misconceptions and mysteries about how these drugs work.
Powerful simulation
The active ingredient in Novo Nordisk’s Ozempic and Wegovy is semaglutide, which belongs to a group of drugs known as glucagon-like peptide 1 receptor agonists, or GLP-1RAs for short. GLP-1 is one of several hormones that play an important role in regulating our body and hunger. It achieves this by using several methods.
When we eat, for example, our blood sugar starts to rise. In response to this, the gut releases GLP-1, which in turn stimulates the production of insulin in the pancreas, which then transports sugar from our blood to cells, lowering blood sugar levels. GLP-1 also slows the rate at which food leaves our stomachs by interacting with the vagus nerve, which helps promote a feeling of fullness as we eat. Certain cells in the brain produce GLP-1 as well, and this brain-derived GLP-1 is thought to reduce our appetite and food cravings that we may have throughout the day.
Scientists first discovered GLP-1 in 1986, and the direct effect it was found to have on insulin production soon led scientists to wonder whether GLP-1 or something similar could be used to treat type 2 diabetes—a condition that appears to be uncontrollable and incurable. high blood sugar levels. Natural GLP-1 does not last very long in our body, however, with a half-life of only minutes. Finally, scientists were able to create lab-made proteins that could use the same receptors as those activated by GLP-1, while lasting longer in our system, GLP-1RAs.
The first GLP-1RA approved for type 2 diabetes was the drug exenatide, which was a synthetic form of a protein (extenin-4) that was first discovered in the slobbery skin of the Gila monster lizard.Heloderma isola). Other GLP-1RAs followed over the years, with semaglutide first approved as the diabetes drug Ozempic in 2017. But the basic principle of these drugs mimic, and increase effectively, the natural activities of GLP-1 has remained the same, according to Andrea Coviello. , an endocrinologist and medical director of the Medical Weight Program at the University of North Carolina.
“When they started producing these synthetic versions and tweaked them a little bit, they just extended the half life,” Coviello told Gizmodo over the phone. Semaglutide in particular has a half-life of a week, more than 13 or more hours of exenatide. One major modification of semaglutide prevents it from being quickly broken down by the DPP-4 enzyme, while another allows it to bind closely to the blood serum protein albumin, which means it can stay in our blood for a long time without being filtered by the kidneys.
Although GLP-1RAs were first developed as a treatment for type 2 diabetes, scientists suspected as early as the 1990s that they could also be used to treat obesity, given the effect of GLP-1 on our hunger and satiety. The first GLP-1RA approved for obesity was liraglutide in 2014, under the name Saxenda, while a higher-dose version of semaglutide was approved under the name Wegovy in 2021.
What’s great about GLP-1s
Although these previous GLP-1 drugs were very important to patients, the arrival of semaglutide really changed the landscape of obesity medicine. In large clinical trials, people taking Wegovy have been shown to lose about 15% of their body weight over a year, more than the usual success seen with diet and exercise alone and exceeding the usual success seen with older obesity drugs. In comparison, people taking Saxenda in the same trial lost about 7.5% of body weight.
Some studies have suggested that obese people produce less natural GLP-1 in response to food, which may help explain their higher weight. Given that, it’s tempting to think that these drugs are simply correcting GLP-1 deficiency in obese people. However, this research is inconclusive, and obesity is often a complex condition with many different interacting factors. It may be more accurate to say that GLP-1RAs are the most powerful defense we can use to address the biological bases of obesity, if not the only one available. That said, people who use these medications often feel relief, often reporting a significant reduction in “food cravings,” or incessant, obsessive thoughts about food.
The years since Wegovy’s approval have reinforced the benefits of GLP-1RAs not only for obesity but 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 them; others have found preliminary evidence that GLP-1RAs can reduce the risk of obesity-related cancers, depression, and possibly even dementia. Many of these benefits appear to be related to the significant weight loss resulting from GLP-1 treatment. Although an overweight person is not necessarily less healthy than the average person, obesity is associated with higher levels of inflammation, high blood pressure, and other physiological changes that may raise our risk of health problems such as type 2 diabetes and heart disease. So losing weight can improve these factors, but that alone does not explain all of the beneficial benefits that may be tied to these medications.
Some studies have suggested that semaglutide can improve heart health even in people who lose a little weight, for example, perhaps because of its effects on reducing blood sugar or inflammation. Another study found preliminary data that semaglutide can reduce people’s cravings for vices such as binge drinking and gambling—an unexpected finding that may be linked to how GLP-1 works in the brain.
As it turns out, the effects of natural GLP-1 on our appetite control seem to come mostly from GLP-1 that comes from the brain, not the gut. And it seems that GLP-1 receptors in the brain are also involved in controlling our response to potentially addictive substances such as cocaine and other drugs, possibly by interacting with dopamine, a neurotransmitter that plays a major role in our reward system, although scientists are not yet sure. about the exact processes involved. Regardless, researchers have begun to conduct large-scale trials of semaglutide not only in alcohol but in other brain-related conditions such as Alzheimer’s.
What’s wrong with GLP-1s
No drug is safe, and GLP-1RA is no exception. Their most common side effects are gastrointestinal symptoms such as nausea, vomiting, and constipation. These can also be explained by the biology of GLP-1, according to Coviello.
So if you have these compounds for a few hours, you may have a tendency for potentially beneficial effects, such as reducing bowel movement-which gives you a better crack at doing an efficient job in digestion. ,” he explained. “But if you then extend that part of life to a day, or now seven days a week, that decreased gut motility is what we think is the cause of this feeling of fullness, and maybe some of the nausea that people experience, and for a long time, constipation, because your bowel movement is slower. .”
Even worse, however, GLP-1 therapy is thought to sometimes cause very slow digestion, which can lead to a condition called gastroparesis. Although gastroparesis is popularly known as stomach paralysis, this term includes any degree of slow emptying of the stomach that is harmful to us. Another serious side effect associated with GLP-1RA use is ileus, or intestinal blockage. Last year, the FDA approved changes to Ozempic’s label to mention the potential risk of ileus after reports of an adverse event, although it did not confirm that ileus was an adverse effect.
Fortunately, ileus and gastroparesis appear to be rare complications of GLP-1RAs. Hard evidence of other possible side effects, such as an increased risk of suicide or severe muscle loss, has not been seen so far, although it is certainly possible that scientists have discovered new health risks that have not yet been established. Currently, GLP-1RAs appear to be safe and effective in most patients who take them, and the more serious gastrointestinal side effects they cause tend to diminish over time.
The future of obesity
While semaglutide and its brand names have become the poster child for this new era in obesity treatment, it is really only the beginning. Eli Lilly’s recently released tirzepatide, which mimics both GLP-1 and another hormone related to the pancreas GIP, has already proven to be more effective than semaglutide, for example. Novo Nordisk and other drug companies are also developing their own, some of which include GLP-1 and two other hunger-related hormones. Others are working to make these drugs easier to take, while one company is researching the possibility of making our cells produce more GLP-1 with a single lifetime dose of gene therapy.
As with all of this research, doctors like Coviello note that these medications cannot address the root causes of why obesity has become a major problem over time. The adult obesity rate in the US is currently around 42%, and the prevalence of obesity has continued to rise in many states even after Wegovy was approved in 2021. Scientists will continue to study and develop these drugs, but that is only one piece of the larger approach needed to deal with this growing public health problem.
“I think what we’re going to see going forward is going to be a lot better and hopefully better tolerated than what we’re seeing right now.” But I think the big question that remains is why have we seen this obesity epidemic in general? That question remains unanswered despite major advances in our understanding of new mechanisms of obesity,” she said. “If we could find out what happened or what changed, and attack that, maybe the answer is fixing that and not relying on better and better drugs that just mimic or reinforce the natural signals in the body that have always been designed to manage metabolism. .”
Semaglutide and other GLP-1RAs have turned out to be even more helpful than we had hoped, and the future looks bright for these drugs. But there are health problems that no drug, no matter how miraculous it seems, can fix on its own.
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