Why do some people not lose weight on semaglutide?

A new study published in Nature analysed nearly 28,000 individuals to understand why responses to GLP-1 drugs such as semaglutide vary so widely.

Some people lose a significant amount of weight.

Others lose very little.

Some stop treatment due to side effects.

So the question is: why does this happen?

Why responses to GLP-1 drugs vary

Medications such as tirzepatide act on:

• appetite

• blood glucose

• satiety signals

• brain pathways (including reward and “food noise”)

Yet the response is far from uniform.

Clinical trials report an average weight loss of around 10% of body weight.

In real-world settings, variability is much greater.

This is where genetics may play a role.

The role of genetics in GLP-1 response

The study, based on data from 23andMe users, identified genetic variants associated with:

greater weight loss

increased risk of gastrointestinal side effects

Specifically, a variant in the GLP-1 receptor gene was associated with approximately 0.7–1.5 kg greater weight loss

But genetics does not explain everything

This point is crucial.

The genetic effect on weight loss is statistically significant but clinically modest.

It does not explain why one person loses 25% of body weight while another loses very little.

This means: genetics contributes, but it is not the main driver

Side effects: a potentially stronger genetic signal

A more relevant finding concerns side effects.

Some genetic variants appear to increase the likelihood of:

• nausea

• gastrointestinal discomfort

• reduced tolerance to the medication

  
  

This may eventually help identify who is more likely to struggle with treatment tolerance

However, this is not yet part of routine clinical practice.

Why do some people not lose weight on semaglutide?

This is one of the most common questions people search for.

The answer is: there is no single explanation.

Key factors include:

• insulin resistance

• metabolic adaptation

• mitochondrial function

• muscle mass

• adherence to treatment

• brain response to the drug

Genetics is only one piece of the puzzle.

The role of the brain and food noise

GLP-1 drugs also act on the brain, reducing what is often described as food noise.

However:

• not everyone experiences this effect to the same degree

• reward pathways differ between individuals

This contributes to the variability in outcomes.

The often overlooked factor: relationship with food

One critical aspect is rarely discussed.

GLP-1 medications can:

✔ reduce appetite

✔ increase satiety

But they do not automatically change:

• emotional eating patterns

• ingrained habits

• the use of food as emotional regulation

This is one reason why some individuals regain weight after stopping the medication.

What this study really means

This study adds an important piece of information, but it does not change the overall picture.

✔ GLP-1 response is multifactorial

✔ genetics plays a limited role in weight loss outcomes

✔ it may be more relevant for side effects

✔ genetic-based personalization is not yet clinically applicable

Conclusion

The real question is not only:

“Will this drug work for me?”

But rather:

“In what metabolic, behavioural, and personal context am I using this medication?”

GLP-1 drugs are powerful tools.

But their real effectiveness depends on the integration of biology, behaviour, and long-term sustainability.

Genetics is part of the story.

It is not the whole story.