Tirzepatide, used in Mounjaro and Zepbound, can produce dramatic weight loss and improvements in blood pressure, cholesterol and blood glucose.
A new analysis of the SURMOUNT-4 trial shows what happens when people stop it.
For most participants with obesity, at least a quarter of the lost weight came back within a year, and many of the health markers slipped in the wrong direction again.
SURMOUNT-4 enrolled adults with obesity who took tirzepatide for 36 weeks in an open-label phase.
- Stopping Mounjaro is linked with weight regain and loss of heart health benefits
- Mounjaro more effective than Wegovy in first comparison trial
- Mounjaro comes out top in battle of the weight loss drugs
Those who completed this phase and lost at least 10% of their starting weight were then randomised for another 52 weeks to:
- Continue tirzepatide, or
- Switch to placebo injections while carrying on lifestyle advice
The new analysis looked specifically at 308 people who switched to placebo.
Researchers grouped them by how much weight they regained between week 36 and week 88:
- Less than 25% of the lost weight regained
- 25% to less than 50%
- 50% to less than 75%
- 75% or more
In the first 36 weeks on tirzepatide:
- Average weight fell by about 21.9%
- BMI dropped by around 8.3 units
- Waist circumference shrank by about 18.3 cm
Cardiometabolic measures also improved:
- Blood pressure came down
- Triglycerides and non-HDL cholesterol dropped
- Haemoglobin A1c, fasting glucose and fasting insulin improved
- Markers of insulin resistance (HOMA2-IR) decreased
So the drug did what it was supposed to do.
What happened after stopping tirzepatide
Once tirzepatide was replaced with placebo:
- Weight regain was common and followed a clear pattern
- About half of participants regained 50% or more of the weight they had lost
- Roughly one in four regained at least 75% of the lost weight
- Nearly 9% ended up heavier than when they started
Only around 4% continued to lose weight with lifestyle measures alone.
The more weight people regained, the more their health markers slid back towards baseline:
- Systolic blood pressure rose by 6.8, 7.3, 9.6 and 10.4 mm Hg across the four increasing regain groups
- Waist circumference crept up by 0.8, 5.4, 10.1 and 14.7 cm
- Triglycerides and non-HDL cholesterol climbed, especially in those with higher regain
- Haemoglobin A1c and fasting glucose increased in step with weight regain
- Insulin resistance (HOMA2-IR) worsened again
Participants who kept their weight regain below 25% held on to most of the cardiometabolic improvements, with no significant worsening in waist circumference, some lipid measures and insulin resistance.
Interestingly, HDL cholesterol dipped during tirzepatide treatment and then rose again after withdrawal in all groups, though that does not cancel out the other changes.
Study: Horn DB et al. JAMA Internal Medicine 2025.
