Ozempic, Wegovy, and its cousins have become the pharmaceutical darlings of the 2020s. These drugs help people lose substantially more weight than diet and exercise alone, while studies have begun to find 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 health?
The connection between poorer health and higher weight has always been more complicated than commonly portrayed. But people living with obesity do face a greater risk of some health problems, and many people do want to lose weight for understandable reasons, such as being able to walk with less knee pain or to sleep more soundly without apnea. Unfortunately, as most anyone who’s tried to trim the pounds can tell you, it’s incredibly difficult to lose a large amount of weight and to keep it off over the long term.
The advent of Ozempic and its ilk has significantly changed that reality, but despite their effectiveness, there’s still lots of misconceptions and mysteries surrounding how these drugs work.
Potent mimics
The active ingredient in Novo Nordisk’s Ozempic and Wegovy is semaglutide, which formally 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 a key role in regulating our metabolism and hunger. It accomplishes this through several mechanisms.
When we eat, for instance, our blood sugar begins to increase. In response to this, the gut releases GLP-1, which in turn stimulates the production of insulin from the pancreas, which then moves glucose from our blood into cells, lowering blood sugar levels. GLP-1 also slows down the emptying of food from our stomachs by interacting with the vagus nerve, helping to encourage a sense of fullness as we’re eating. Certain cells in the brain produce GLP-1 as well, and this brainy GLP-1 is thought to dampen our appetite and the food cravings that we might have throughout the day.
Scientists first discovered GLP-1 in 1986, and the direct effect that it was found to have on insulin production soon made scientists wonder if GLP-1 or something very similar could be used to treat type 2 diabetes—a condition characterized by uncontrolled and chronically high levels of blood sugar. Natural GLP-1 doesn’t last very long in our body, though, with a half-life of only minutes. Eventually, scientists were able to develop lab-made proteins that could activate the same receptors that GLP-1 does, while lasting much longer in our system, the GLP-1RAs.
The very first GLP-1RA approved for type 2 diabetes was the drug exenatide, which was the synthetic version of a protein (extenin-4) famously first found in the slobbery venom of the Gila monster lizard (Heloderma suspectum). 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 mimicking, and effectively boosting, the natural functions 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 modifying them a little bit, they really just extended the half life,” Coviello told Gizmodo over the phone. Semaglutide in particular boasts a half-life of around a week, well above the 13 or so hours for exenatide. One major modification in semaglutide prevents it from being rapidly broken down by the DPP-4 enzyme, while another allows it to closely bond to the blood serum protein albumin, meaning it can stay in our blood longer without being filtered out by the kidneys.
Though GLP-1RAs were first developed as treatments for type 2 diabetes, scientists suspected as early as the 1990s that they could also be used to treat obesity, given GLP-1’s effect 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 good about GLP-1s
As valuable as these earlier GLP-1 drugs were for patients, the arrival of semaglutide truly changed the landscape of obesity medicine. In large-scale clinical trials, people taking Wegovy were shown to lose around 15% of their body weight over a year’s time, well above the typical success seen with diet and exercise alone and surpassing the typical success seen with older obesity drugs. For comparison, people taking Saxenda in a similar trial lost about 7.5% body weight.
Some research has suggested that people with obesity 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 fixing a GLP-1 deficiency in obese people. However, this research isn’t conclusive, and obesity tends to be a complex condition with many different interacting factors. It might be more accurate to say that GLP-1RAs are one especially potent lever that we can use to address the biological underpinnings of obesity, if not the only one available. That said, individuals taking these drugs do commonly feel a palpable sense of relief, often reporting a dramatic decrease in “food noise,” or constant, intrusive thoughts about food.
The years since Wegovy’s approval have only solidified the benefits of GLP-1RAs for not only obesity but many other health conditions. Large studies have found that semaglutide can reduce the risk of heart and kidney problems in obese people at higher risk for them; others have found early evidence that GLP-1RAs could reduce the risk of obesity-related cancers, depression, and possibly even dementia. Much of these benefits seem to be tied to the substantial weight loss caused by GLP-1 therapy. While someone with obesity is not necessarily unhealthier than the average person, obesity is associated with higher levels of inflammation, high blood pressure, and other bodily changes that can raise our risk of health problems such as type 2 diabetes and heart disease. So losing weight can improve these factors for the better, but that alone doesn’t explain every rosy benefit possibly tied to these drugs.
Some research has suggested that semaglutide can improve heart health even in people who lose little weight, for instance, possibly due to the effects it has on reducing blood sugar or inflammation. Other studies have found preliminary data that semaglutide can tamp down people’s cravings for unhealthy vices like heavy alcohol drinking and gambling—an unexpected phenomenon likely linked to how GLP-1 works in the brain.
As it turns out, the effects of natural GLP-1 in regulating our food intake seem to predominantly come from the GLP-1 derived from the brain, not the gut. And it appears that GLP-1 receptors in the brain also play a part in regulating our response to potentially addictive stimuli like cocaine and other drugs, possibly through interacting with dopamine, a neurotransmitter heavily involved in our reward system, though scientists are still not sure about the exact mechanisms involved. Either way, researchers have begun to conduct larger trials of semaglutide for not only alcoholism but other brain-related conditions like Alzheimer’s.
What’s bad about GLP-1s
No drug comes risk-free, and GLP-1RAs are no exception. Their most common side effects are gastrointestinal symptoms like nausea, vomiting, and constipation. These too can be explained by the biology of GLP-1, according to Coviello.
“So when you have these compounds around for a couple of hours, you might have a tendency for effects that are possibly beneficial, like slowing down gut motility—a little bit that gives you a better crack at doing a more efficient job at digesting foods,” she explained. “But if you would then extend that half life to a day, or now seven days a week, that slowing in the gut motility is what we think is behind this sense of fullness, and possibly some of the nausea that people experience, and in the longer term, constipation, because your gut motility is a little bit slower.”
More seriously, though, GLP-1 therapy is thought to sometimes cause too much slowed digestion, which can result in a condition called gastroparesis. Though gastroparesis is more colorfully known as stomach paralysis, the term covers any degree of slowed gastric emptying that’s harmful to us. Another serious adverse effect associated with GLP-1RA use is ileus, or intestinal blockage. Last year, the FDA mandated a change to Ozempic’s label to mention the potential risk of ileus following adverse event reports, though it stopped short of confirming ileus as a side-effect.
Thankfully, ileus and gastroparesis appear to be rare complications of GLP-1RAs. Strong evidence for some other potential serious side-effects, such as increased suicide risk or severe muscle loss, hasn’t materialized to date, though it’s certainly possible that scientists will find new health risks not currently established. For now, GLP-1RAs do appear to be safe and effective for the majority of patients taking them, and even the more unpleasant gastrointestinal side effects they cause tend to wane 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’s really only the start. Eli Lilly’s recently released tirzepatide, which mimics both GLP-1 and another hunger-related hormone GIP, has already proven to be more effective than semaglutide, for instance. Novo Nordisk and other drug companies are also developing their own successors, some of which are combining GLP-1 with two other hunger-related hormones. Others are working to make these drugs easier to take, while one company is even researching whether it’s possible to make our cells naturally produce more GLP-1 with a single lifetime dose of gene therapy.
As revolutionary as all this research could be, doctors like Coviello notes that these drugs aren’t able to tackle the root causes of why obesity has become a bigger issue over time. The adult obesity rate in the U.S. is currently around 42%, and the prevalence of obesity has continued to rise in many states even since the approval of Wegovy in 2021. Scientists will continue to study and improve these drugs, but that’s only one piece of the larger approach needed to address this growing public health problem.
“I think what we’re going to see moving forward is even going to be more elegant in approach and hopefully even better tolerated than what we are seeing right now. But I think the big question that still remains is why we have seen this epidemic of obesity in general? That question has not been answered despite really significant advancements in our understanding of the new mechanisms behind excess weight gain,” she said. “If we could figure out what happened or what changed, and attack that, then maybe the answer is fixing that and not necessarily counting on better and better drugs that really just mimic or intensify natural signals in the body that were always designed to handle metabolism.”
Semaglutide and other GLP-1RAs have turned out to be even more useful than we hoped, and the future looks bright for these medications. But there are some health issues that no drug, no matter how miraculous it seems, can fix all on its own.
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