No Paywall:

“The Ozempic Plateau Everyone hits a weight-loss plateau, but the race is on for next-generation drugs that can help patients lose even more weight.

The latest weight-loss drugs are rightly hailed as game changers for obesity, but in an important way, they are just like every other method of managing weight: They work only to a point for weight loss. The pounds melt off quickly at first and then gradually and then not at all. You can’t lose any more no matter what you do. You’ve hit the weight-loss plateau.

It happens with dieting. It happens with bariatric surgery. And it happens now with both semaglutide (better known as Ozempic or Wegovy, depending on whether it’s prescribed for diabetes or weight loss) and tirzepatide (better known as Mounjaro or Zepbound). Weight loss triggers a set of powerful physiological changes in the body, which evolved over millions of years to keep us alive through periods of food scarcity. “Everybody plateaus,” says Jamy Ard, an obesity doctor at Wake Forest University. Exactly when varies quite a bit from person to person, but it happens after losing a certain percentage of body weight—meaning some people might plateau while still meeting the criteria for obesity.

For Wegovy, it’s after losing, on average, 15 percent, usually more than a year into starting the drug. For Zepbound, it’s about 20 percent. These numbers are higher than is sustainable through diet and exercise alone, but they also do not reach the 30 percent achievable via the gold standard of bariatric surgery.

These differences matter because they suggest that the level of the plateau is not permanently fixed. Recent advances in understanding the gut hormones that these drugs are designed to mimic hint at a possibility of even more powerful weight-loss drugs. Scientists are now testing ways to push the plateau down further; a drug could one day be even more effective than bariatric surgery.

All of this raises an unsettled question: “How much weight loss is enough?” says Jonathan Campbell, who studies gut hormones at Duke. In studies, even 5 to 15 percent weight loss can substantially reverse high blood pressure, high blood sugar, and high cholesterol. Yet a patient who starts at 375 pounds with a BMI of 60 might still find themselves ineligible for a joint replacement that requires a BMI below 40, flawed as BMI may be. Or they may simply want to look thinner. The explosion of weight-loss drugs has reopened thorny questions about how they should be used, but nevertheless, pharmaceutical companies are racing ahead to develop more and more powerful ones.

Weight loss is easiest at the beginning, before your body starts actively working against it. “Your brain doesn’t know you’re trying to lose weight on purpose,” Ard says. And once it notices, “it thinks that something is wrong.” So your body tries very, very hard to compensate.

First of all, you become hungrier, obviously. And not just because you want to eat as much as you did before; you actually want to eat more than you did prior to losing weight. “With every one kilogram you lose, your appetite goes up above baseline by 90 or so calories per day,” says Kevin Hall, who studies metabolism at the National Institute of Diabetes and Digestive and Kidney Diseases. At the same time, your body looks for ways to conserve energy. Your muscles work more efficiently, for example, Ard says, so walking that normally burned 100 calories might now burn only 90. By making you want to eat more and burning fewer calories, your body is eventually able to slow weight loss down to zero. Here is your plateau. This is, all told, a remarkably elegant and robust system, if what you wanted to do is to maintain your weight.

If you’re in fact trying to lose more weight, the plateau is psychologically frustrating. The same diet, the same exercise routine, the drug on which you were just losing weight will seem to have stopped working—but they haven’t. (If they did actually stop working, you would be regaining weight.) But your body is now fighting so hard against the weight loss that it requires a persistent effort just to keep the weight off, Hall says. Should you ease up, the weight will come right back, as seen in yo-yo dieting or weight regain after stopping Wegovy or Zepbound.

The only way to get past a plateau is to up the intensity or number of interventions. Doctors might recommend, for example, bariatric surgery and a weight-loss drug. But in the future, novel drugs might be able to pharmacologically up the intensity. The progression from Wegovy to the more effective Zepbound has in fact already brought us one step closer.

Wegovy and Zepbound both belong to a class of drugs that mimic a gut hormone called GLP-1. Both of these drugs bind GLP-1 receptors in the brain, which seems to reduce hunger. Zepbound goes a step further, though. It can also bind receptors for a second gut hormone, called GIP. Years ago, researchers noticed that bariatric surgery changes the balance of gut hormones in the body, including GLP-1 and GIP. This—and not just the physical shrinking of the stomach—is now understood to be a key driver of weight loss, to the point that bariatric surgery is sometimes called “metabolic surgery.” These observations inspired research into drugs that target not just GLP-1 but also GIP and other hormones. Essentially, they’re performing metabolic surgery with a drug rather than a scalpel.

Exactly why Zepbound outperforms Wegovy is still unclear. One obvious hypothesis is that it mimics a second gut hormone; the more hormonal pathways it can influence, perhaps, the more body parts it affects and the more weight loss it triggers. And a recent clinical trial of retatrutide, a further modified derivative of Zepbound that mimics a third hormone called glucagon, demonstrated even greater weight loss: 24 percent at the highest dose.

A second hypothesis suggests that the difference between Wegovy and Zepbound still goes back to GLP-1. Although both drugs bind that receptor, they tickle it slightly differently, setting off slightly different chain reactions. Wegovy seems to also activate some cellular machinery that acts as a break, possibly limiting its efficacy. This suggests another strategy for fine-tuning gut-hormone drugs: Companies have so far focused on trying to design one drug that binds to multiple hormone receptors, like a master key that can open three different locks. This was a practical choice, Campbell says, because trying to study three separate new drugs in clinical trials would be a logistical “nightmare.” But the optimal combination for weight loss might actually require individual keys that can jigger individual receptors in just the right way—that is, a double or triple combination of drugs.

It may also eventually be possible to keep increasing the dosage of GLP-1 drugs to push the weight-loss plateau down. Right now, the dose is limited by what people are willing to tolerate. The drugs can cause severe nausea, vomiting, and diarrhea, so they have to be ramped up slowly over many weeks to induce tolerance and minimize side effects. But Novo Nordisk is trialing the drug in Wegovy at up to 16 milligrams a week, more than six times the current maximum dose. Tinkering with other gut-hormone pathways could also help with side effects. GIP receptors, for example, are found in neurons whose activation might suppress nausea, which may in part be why Zepbound seems to have slightly milder side effects.

Zepbound is likely the first of many leveling-ups from single-action GLP-1 drugs. Even as the science advances, no safe method of losing weight is meant to eliminate the weight-loss plateau—and indeed, you wouldn’t want to keep losing weight indefinitely. But lose more weight? Pharmaceutical companies are betting on a market for that. With obesity drugs projected to become a $100 billion industry by 2030, they are eager for a slice of that massive pie. “The dollar signs are so big now,” Campbell says. Zepbound is the newest weight-loss drug on the block, but it too may eventually be old news.”