A report says participants gained 14% after stopping tirzepatide. Another says people regained two-thirds of their earlier loss after semaglutide ended.[1][2] Did the second group regain vastly more? Each percentage uses a different denominator, and the study designs differ too. Understanding those differences changes how a withdrawal headline reads.
SURMOUNT-4 starts its comparison after treatment has begun
SURMOUNT-4 enrolled 783 adults with obesity, or overweight with a weight-related complication, excluding diabetes. Everyone initially received injected tirzepatide during a 36-week open-label lead-in: participants and investigators knew which treatment was being given. Only afterward were 670 participants randomly assigned to continue tirzepatide or switch to placebo for another 52 weeks, under double-blind conditions.[1]
That second assignment creates the withdrawal experiment. Both groups had already received active treatment, and lifestyle counseling continued throughout. The comparison therefore estimates the effect of continuing versus withdrawing tirzepatide within that selected population and setting.[1][3]
Selection matters. The label reports that 14.4% of those starting treatment discontinued before randomization, most commonly because of adverse events. The randomized results consequently do not describe every first-time user, including those unable to complete the lead-in.[3]
What continuing and withdrawing actually produced
The 670 randomized participants had lost an average 20.9% of their starting weight during the lead-in. From week 36 to week 88, the continuing group lost a further 5.5% on average, while the placebo-switch group gained 14.0%. The reported between-group difference was 19.4 percentage points in favor of continued treatment.[1]
A separate maintenance measure asks how much of the earlier loss remained. At week 88, 89.5% of continuing participants maintained at least 80% of their lead-in loss, compared with 16.6% of those switched to placebo.[1]
Withdrawal also did not erase all average progress. From original enrollment to week 88, mean weight reductions were 25.3% with continuation and 9.9% with the switch to placebo.[1] Substantial regain and remaining below the original weight can coexist.
STEP 1 followed people after two interventions ended
The main STEP 1 trial randomized 1,961 adults without diabetes to injected semaglutide or placebo alongside lifestyle intervention. At week 68, both study treatment and structured lifestyle intervention ended. The exploratory extension followed a selected subset from participating countries and sites for another year; its analysis set included 327 people.[2]
This extension did not randomize participants anew to stop or continue semaglutide. Neither group was assigned continued active treatment. Because lifestyle support ended alongside medication, the extension cannot isolate the contribution of withdrawing each component.[2]
In this subset, mean weight loss during semaglutide treatment was 17.3%. Over the off-treatment year, participants regained 11.6 percentage points of baseline body weight, leaving a reported average 5.6% loss at week 120. The former placebo group regained 1.9 percentage points after initially losing 2.0%.[2] These are exploratory observations, not a randomized estimate of stopping versus continuing.
Read the starting weight before reading the percentage
SURMOUNT-4's 14.0% increase uses week 36 weight as its denominator, after the lead-in loss. STEP 1's roughly two-thirds summary compares the 11.6 percentage points regained with the 17.3% previously lost, both referenced to original baseline.[1][2] The numbers therefore cannot be placed side by side as equivalent regain rates.
A simple arithmetic illustration helps: a hypothetical weight falling from 100 units to 80 and then rising by 10% reaches 88. That increase recovers eight of the twenty units lost, or 40% of the earlier loss. This illustrates denominators; it does not reconstruct either trial's participant data.
| Reading question | SURMOUNT-4 | STEP 1 extension |
|---|---|---|
| Where does withdrawal begin? | Week 36, after active lead-in.[1] | Week 68, after the main trial.[2] |
| What is compared? | Randomized continuation versus placebo switch.[1] | Follow-up by original semaglutide or placebo assignment.[2] |
| Does lifestyle support continue? | Yes.[3] | Structured trial intervention ends.[2] |
| What does the headline measure? | Weight change relative to randomization weight.[1] | Fraction of prior baseline-relative loss regained.[2] |
Average trajectories leave important questions open
In STEP 1, 48.2% of former semaglutide participants with a measured week 120 weight remained at least 5% below baseline: 95 of 197 people. That denominator matters because the full semaglutide extension analysis group contained 228 participants.[2] An average cannot reveal whether a particular individual regained little, much or all of an earlier loss.
Most cardiometabolic improvements moved toward baseline after withdrawal, although some benefits remained. Whether slowing regain near the end represented a lasting plateau required longer follow-up.[2] These results do not automatically extend to different formulations, populations or treatment histories, or supply personal stopping plans.
Safety remains a separate part of the evidence
SURMOUNT-4's most common adverse events were gastrointestinal and mostly mild to moderate.[1] The tirzepatide label also warns about severe gastrointestinal reactions, dehydration-related kidney injury and acute pancreatitis. Its boxed warning concerns thyroid C-cell tumors in rats; human relevance is unknown. Rodent findings are not proof that tirzepatide causes human thyroid cancer.[3]
Trial outcomes cannot establish laboratory research materials' suitability for human use. FDA describes dosing errors, fraudulent products and unapproved drugs marketed to consumers under research-use labels.[4] Analytical testing does not itself establish clinical safety, appropriate formulation or sterility for injection. Laboratory research materials should not be consumed or self-administered. This does not presume every reagent is contaminated; research characterization and evidence supporting a medicine answer different questions.[4]
Source note: This article uses the original SURMOUNT-4 abstract, the full STEP 1 extension paper, relevant current Zepbound sections and FDA safety information retrieved October 23, 2026. The SURMOUNT-4 full paper was not accessed. STEP 1 did not systematically collect adverse events during its extension, so that follow-up cannot establish absence of harms. This is editorial source review, not medical review or a Chudik experiment.