The latest weight-loss drugs are rightfully hailed as game-changers for obesity, but in one important way, they're just like every other way to manage your weight. In other words, it only works to the point where weight loss is possible. The pounds melt quickly at first, then gradually, and then not at all. Whatever you do, you can't lose any more. You've reached a weight loss plateau.
This is what happens when you diet. This is what happens when you have bariatric surgery. And this currently happens with both semaglutide (better known as Ozempic or Wegovy, depending on whether it is prescribed for diabetes or weight loss) and tirzepatide (better known as Mounjaro or Zepbound). Weight loss triggers a series of powerful physiological changes in the body that have evolved over millions of years to keep us alive during periods of food scarcity. “Everyone is at a plateau,” says Jamy Ard, an obesity specialist at Wake Forest University. The exact timing varies from person to person, but it occurs after a certain percentage of weight has been lost. This means that some people may plateau while still meeting the criteria for obesity.
For Wegovy, an average loss of 15% occurred and typically occurred more than a year after starting drug use. For Zepbound, it's about 20%. This number is higher than is sustainable through diet and exercise alone, but it does not even reach the 30% that can be achieved through standard bariatric surgery.
These differences are important because they suggest that the level of the plateau is not permanently fixed. Recent advances in our understanding of gut hormones suggest that these drugs may have the potential to be even more powerful weight loss drugs. Scientists are now testing ways to push the plateau further down. One day, drugs may be even more effective than bariatric surgery.
All of this raises the disturbing question, “How much weight loss is enough?” says Jonathan Campbell, who studies gut hormones at Duke. Studies show that losing just 5 to 15 percent of your body weight can significantly reverse high blood pressure, high blood sugar, and high cholesterol. However, a patient who starts at 375 pounds and has a BMI of 60 is not eligible for joint replacement surgery, which requires a BMI of less than 40, and the BMI may also be at fault. Or maybe you simply want to look slimmer. The explosion of weight loss drugs has again raised tricky questions about how they should be used. Nonetheless, pharmaceutical companies are racing to develop increasingly powerful drugs.
Losing weight is easiest in the beginning, before your body begins to actively work against it. “Your brain doesn’t know that you’re intentionally trying to lose weight,” says Ard. And once you notice, “I think something is wrong.” So your body works very hard to compensate.
First of all, of course you get hungry. And it's not just because I want to eat as much as before. You actually want to eat more than you did before you lost the weight. “For every pound you lose, your appetite increases by about 90 calories per day above baseline,” says Kevin Hall, who studies metabolism at the National Institute of Diabetes and Digestive and Kidney Diseases. At the same time, the body finds ways to conserve energy. For example, a walk that would normally burn 100 calories may now burn only 90 calories because your muscles work more efficiently, Ard says. By making you want to eat more and burn fewer calories, your body can eventually slow weight loss down to zero. Here is your plateau. All told, this is an incredibly elegant and robust system if what you want to do is maintain your weight.
If you're actually trying to lose more weight, plateauing can be psychologically frustrating. The same diet, same exercise routine, and medication you just used to help you lose weight will seem to have stopped working. But that's not the case. (In fact, if it stops working, you'll gain the weight back.) But now that your body is fighting so hard against weight loss, it will take sustained effort to keep it off, Hall says. When you relax, the weight comes right back, as seen with yo-yo dieting or weight regain after stopping Wegovy or Zepbound.
The only way to overcome plateaus is to increase the intensity or frequency of interventions. Your doctor may recommend bariatric surgery, for example. and Weight loss pills. However, in the future new drugs may offer increased pharmacological strength. The evolution from Wegovy to a more effective Zepbound is actually already one step closer.
Both Wegovy and Zepbound belong to a class of drugs that mimic a gut hormone called GLP-1. Both of these drugs appear to reduce hunger by binding to GLP-1 receptors in the brain. But Zepbound goes one step further. It can also bind to a second gut hormone receptor called GIP. A few years ago, researchers discovered that bariatric surgery changes the balance of gut hormones in the body, including GLP-1 and GIP. This is not just the physical contraction of the stomach, but is now understood to be a major driver of weight loss, to the point where bariatric surgery is sometimes called “metabolic surgery.” These observations have inspired research on drugs targeting not only GLP-1, but also GIP and other hormones. Essentially, they are performing metabolic surgery using drugs rather than a scalpel.
The exact reason why Zepbound outperforms Wegovy is still unclear. One obvious hypothesis is that it mimics second gut hormones. The more hormonal pathways it can influence, the more body parts it can affect and the more weight loss it can cause. And a recent clinical trial of ritatrutide, a further modified derivative of Zepbound that mimics a third hormone called glucagon, showed an even greater weight loss of 24% at the highest dose.
The second hypothesis suggests that the differences between Wegovy and Zepbound still go back to GLP-1. Both drugs bind to those receptors, but stimulate them slightly differently, triggering slightly different chain reactions. Wegovy also appears to limit its efficacy by activating some cellular machinery that serves a resting role. This presents another strategy for fine-tuning enterohormonal drugs. Companies have so far focused on designing one drug that binds to multiple hormone receptors, like a master key that can open three different locks. Campbell said this was a practical choice because studying three separate new drugs in clinical trials would be a logistical “nightmare.” But the optimal combination for weight loss may actually require individual keys, i.e. a double or triple combination of drugs, that can get individual receptors moving in the right way.
It may eventually be possible to continue increasing the dose of the GLP-1 drug to lower the weight loss plateau. Currently, doses are limited by what people are willing to tolerate. Because the drug can cause severe nausea, vomiting, and diarrhea, the dose should be increased slowly over several weeks to induce tolerance and minimize side effects. But Novo Nordisk is testing the drug in Wegovy at up to 16 mg per week, more than six times the current maximum dose. Modulating other gut-hormonal pathways may also help alleviate side effects. For example, GIP receptors are found on neurons that can be activated to suppress nausea, which may be partly why Zepbound has slightly milder side effects.
Zepbound is likely to be the first of many level-ups of single-acting GLP-1 drugs. Even as science advances, there is no safe weight loss method that can eliminate weight loss plateaus. In reality, you don't want to maintain your weight loss indefinitely. But lose more weight? Pharmaceutical companies are investing in the market for this purpose. With the obesity treatment industry expected to grow to $100 billion by 2030, they're hungry for a piece of that huge pie. “Now the dollar signs have become too big,” Campbell says. Zepbound may be the newest weight loss drug, but it may eventually become old news.