Do weight loss drugs work? You’ll still plateau, studies suggest


Whether you’re shedding pounds with the help of effective new medicines, slimming down after weight loss surgery or cutting calories and adding exercise, there will come a day when the numbers on the scale stop going down, and you hit the dreaded weight loss plateau.


In a recent study, Kevin Hall, a researcher at the National Institutes of Health who specializes in measuring metabolism and weight change, looked at when weight loss typically stops depending on the method people were using to drop pounds. He broke down the plateau into mathematical models using data from high-quality clinical trials of different ways to lose weight to understand why people stop losing when they do. The study published Monday in the journal Obesity.


What he found is that part of the reason that gastric bypass surgery and new weight loss drugs such as Wegovy and Zepbound are so effective is because they double the time it takes to hit a plateau. People are able to lose weight for longer than by cutting calories alone.


The body regulates weight by trying to maintain an equilibrium between the calories we eat and the calories we burn. When we expend or cut calories, and start burning our stored energy, appetite kicks in to tell us to eat more. Hall’s studies have shown that the more weight a person loses, the stronger appetite becomes until it counteracts, and sometimes completely undoes, all the hard work they’ve done to lose in the first place.


This feedback mechanism was valuable for our hunter-gatherer ancestors, but it doesn’t work so well for modern humans who have easy access to energy-dense ultra-processed foods.


Plateaus at different points


To study the trajectory of weight loss using calorie restriction alone, Hall modelled the observed weight loss in the CALERIE study, which randomly assigned 238 adults to either two years of following a 25% calorie restriction diet or eating as they normally would. The study ran from 2007 to 2010 and was sponsored by the NIH. The adults in the group that cut calories lost on average about 16 pounds. The group that followed their normal diets gained about 2 pounds.


Though the people who took part in the CALERIE study kept up their efforts for two years, their weight loss stopped somewhere around the 12-month mark, as their appetite ramped up to counteract it.


Hall notes that his study deals in averages. The timing of a weight loss plateau may vary for individuals.


Hall’s model predicted that in order to achieve the weight loss reported in that study, people whose diets started at 2,500 calories per day had to cut just over 800 calories a day. Their bodies responded by prompting them to add to their daily caloric intake an estimated 83 calories for every kilogram of weight they lost.


A kilogram is about 2.2 pounds. For every 2.2 pounds of weight participants lost, their appetite responded by asking for 83 more calories a day. The average weight loss reported in the study was 7.5 kilograms, or 16 pounds, which would mean that at their lowest weights, they were feeling the need to eat 622 more calories a day more than before they started losing weight.


But they weren’t actually eating 622 more calories a day — instead, that’s the extra amount of appetite they were feeling, even as they’re putting in the same amount of effort as they did in the beginning to cut 800 calories a day.


At the end of the study, Hall said, participants were working as hard as they did in the beginning to resist food, but only managing to cut about 200 calories a day instead of the 800 they were shooting for. That brought their weight loss to a halt.


Dr. Christopher Gardner, director of nutrition studies at the Stanford Prevention Research Center, previously told CNN this feedback mechanism is why weight loss gets harder the more you lose.


“Because people’s bodies react to that, and they become more metabolically efficient. And so the same calorie deficit won’t do it for you. That’s why people’s weight loss starts to plateau,” Gardner told CNN Chief Medical Correspondent Dr. Sanjay Gupta in the “Chasing Life” podcast.


In Hall’s model, as people in the CALERIE study lost more weight, their appetites roared back, and around the 12-month mark, they stopped losing weight.


The drugs semaglutide and tirzepatide, which mimic gut hormones to help people lose weight, prompted greater caloric restriction. For semaglutide, the active ingredient in Wegovy, Hall’s model predicted that as people gradually increased their dose in the study, they went from eating about 600 fewer calories a day to 1,300 fewer calories a day at the highest dose. For tirzepatide, the active ingredient in Zepbound, the number of calories people cut from their diet each day increased from 830 on the lowest dose to 1,560 on the highest dose tested in the study.


But crucially, the drugs didn’t merely have an effect on the number of calories people cut from their diets. They also lowered the number of calories their bodies were prompting them to eat back as they lost weight — in effect, weakening their appetites. For Wegovy, people only wanted to eat back about 49 calories daily for every kilogram of weight they lost. For Zepbound, that number was 48. By cutting their appetites by about half, they were able to keep losing weight for longer, an extra year on average compared with calorie restriction alone. People taking weight loss drugs generally stopped losing weight around the two-year mark.


Weight loss surgery had the strongest effect of all, prompting people to cut about 3,600 calories from their diets each day, and only eat back 58 calories for every kilogram they’d lost every day. People who’d had weight loss surgery also had another year before their reached their plateau, suggesting that the surgery turned down their appetite significantly.


More interventions might be necessary


Hall says there are several important insights from this study. The first, he said, is drugs such as Wegovy and Zepbound and interventions like weight loss surgery, lengthen the time it takes to hit a plateau, but they don’t stop it from happening completely.


“What’s happening is that they still experience an increase in appetite, the more weight that they lose,” Hall said.


“If they had no appetite circuit, in other words, the drug just kind of kicked in and their intake stayed at this very low level. It would take many, many years for them to reach a plateau and they would lose, you know, an exorbitant amount of weight,” Hall said.


While it may stymie dieters, the appetite feedback circuit is actually a good thing, he said. It would be dangerous if a drug or treatment got rid of appetite entirely. If that happened, a person might stop eating entirely until they died.


Hall said the study also helps to refine some ideas about why people stop losing weight.


For example, one theory has been that weight loss damages metabolism, so people end up burning far fewer calories at rest than when they started and can regain weight very easily.


Hall says metabolism does drop after weight loss, “but not anywhere near the amount that will be required to explain the timing or magnitude of the weight loss plateau,” he said.


Hall says the study also seems to disprove the notion that the drugs eventually stop working. “I think that’s also incorrect,” Hall said.


“Our modelling suggests that the reason for the plateau is because that’s the point at which the drugs’ effect has been matched by the increase in appetite,” he said.


Sometimes people hit a plateau well before they’ve reached their goal weight, which can be extremely frustrating.


Hall said in situations like that, people may have to add interventions to increase their effect.


“Another very common thing now is that people who didn’t lose as much weight from bariatric surgery as they thought, will go on one of the GLP-1 receptor agonist so they’re adding interventions on top of each other,” Hall said.


Whatever route you choose, “a persistent effect is required to maintain the weight loss,” Hall said. So it’s a good idea to consider whether you can keep doing what you’re doing for the long haul.


People who hit a plateau after cutting calories can likely bust through it by restricting calories even further or adding exercise to their routine.


“The whole point here is that whatever you do, you have to keep doing it. And so you’ve gotta be happy with that lifestyle intervention for the rest of your life. Otherwise, it’s not going to have the added benefit,” Hall said.

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