The first wave of GLP-1 stories was about what the drugs could do. The second wave is about what happens after. As millions of people have started semaglutide or tirzepatide, a practical question has moved to the center of obesity medicine. Is this a course of treatment, like an antibiotic, or a long-term therapy, like a blood pressure pill?
The trial data points firmly toward the second answer. That is not a reason to avoid these drugs. It is a reason to start them with a plan.
How well they work
In the STEP 1 trial1, 1,961 adults with obesity or overweight plus a weight-related condition took weekly semaglutide 2.4 milligrams or a placebo for 68 weeks, alongside lifestyle counseling. The semaglutide group lost an average of about 15 percent of body weight. The placebo group lost about 2 percent.
Tirzepatide, which acts on both GLP-1 and GIP receptors, pushed further. In SURMOUNT-14, adults on the highest dose lost about 21 percent of body weight on average over 72 weeks.
The benefits extend beyond the scale. The SELECT trial5 enrolled more than 17,000 adults with established cardiovascular disease and overweight or obesity, but no diabetes. Semaglutide reduced the combined rate of cardiovascular death, heart attack and stroke by 20 percent compared with placebo.
The data on stopping
The clearest look at discontinuation comes from two follow-up studies.
In the STEP 1 extension2, a subset of 327 participants was followed for a year after everyone stopped their assigned treatment and lifestyle program at week 68. People who had taken semaglutide had lost an average of 17.3 percent of body weight while on the drug. One year after stopping, they had regained about two-thirds of it. Improvements in blood pressure, blood sugar and cholesterol drifted back toward where they started.
STEP 43 asked the question in a cleaner way. All participants took semaglutide for 20 weeks and lost about 10.6 percent of body weight. Then they were randomly split. Those who kept taking the drug lost about 7.9 percent more over the next 48 weeks. Those switched to placebo regained about 6.9 percent.
These drugs do not cure obesity. They treat it, in the same way a statin treats high cholesterol.
The researchers' interpretation was direct. Obesity behaves like a chronic disease. When the treatment stops, the biology that drove weight gain in the first place, including appetite signals that ramp up after weight loss, comes back.
View the data
| Time point | Placebo | Semaglutide |
|---|---|---|
| Start | 0% | 0% |
| Week 68 | -2.0% | -17.3% |
| Week 120 | -0.1% | -5.6% |
Source: Wilding et al., Diabetes, Obesity and Metabolism, 2022
What that means in practice
None of this means stopping is always wrong. People stop for cost, side effects, supply problems, pregnancy plans or simply preference. What the data suggests is that stopping should be a planned transition rather than an abrupt end.
Clinicians are increasingly approaching this in a few ways. Some patients taper to a lower maintenance dose rather than stopping outright. Some extend the interval between doses. Others step down while deliberately strengthening the habits that help hold weight, particularly regular physical activity, which is consistently one of the best predictors of weight maintenance. None of these strategies has the depth of evidence that the main trials do, so they work best as monitored experiments with a clinician rather than solo adjustments.
The muscle question
Weight lost on a GLP-1 is not all fat. In a body composition substudy of STEP 1, close to 40 percent of the weight lost was lean mass, a category that includes muscle along with water and organ tissue. That ratio is broadly similar to what happens with other forms of significant weight loss, but the speed and scale of GLP-1 weight loss make it more consequential, especially for older adults who are already fighting the slow drift of sarcopenia.
The countermeasures are not exotic. Adequate protein, often in the range of 1.0 to 1.2 grams per kilogram of body weight for older adults unless kidney disease limits it, matters more when appetite is suppressed and meals get small. Resistance training two or three times a week gives the body a reason to hold on to muscle. A body composition scan at the start and at intervals shows whether the plan is working.
Questions worth asking before you start
A good GLP-1 consultation covers more than the dose schedule. It should cover what success looks like beyond weight, such as blood pressure, glucose, liver health and fitness. It should include a nutrition plan for eating less while still eating enough protein, fiber and micronutrients. It should address side effects, which most often are nausea, constipation and other digestive symptoms that tend to ease over time. It should have a strategy for the long term, including what happens if insurance coverage changes.
The trials also leave real gaps. Most stopping studies ended treatment abruptly, while many people in the real world taper, skip doses when supplies run short or switch drugs. Researchers are only beginning to study those patterns. Until that data arrives, anyone planning to stop should do it with a clinician who can track weight, blood pressure and glucose for the months that follow.
