Do genetics affect your response to weight loss jabs?

Why don't some people respond as well to GLP-1s?

Like with any medication, people can respond to GLP-1s differently. Some are highly sensitive responders, meaning they respond really well even to lower doses, and may not need to move up doses at all.

Others, though, need to move to the highest dose to see the full (or any) results. And, unfortunately, for a smaller group, the medication doesn’t seem to work, even at the maximum dose. This lack of response can come down to a few different causes, including GLP-1 receptor resistance.

Medically reviewed by

Craig Marsh, Independent Prescriber

Variations in the GLP1R gene

This may sound a bit technical, but bear with us, it’s actually pretty straightforward. GLP-1s work by binding to receptors called GLP-1 receptors, which play a role in many processes in the body, including:

Regulating blood sugar levels
Slowing down how quickly food leaves the stomach
Reducing appetite
Supporting heart health
Improving cholesterol levels
Improving brain function
Reducing inflammation

These receptors are encoded in a tiny part of your DNA called the GLP1R gene. But this gene doesn’t look exactly the same for everyone. Some people have certain variations in it that can:

change how well GLP-1s bind to the GLP-1 receptors (and how well they work as a result)
affect some of the GLP-1 effects, like insulin secretion and how quickly the stomach empties (which can influence your blood sugar levels and appetite)
help explain why some people see better results from these medications than others

Baseline metabolism

Basal metabolic rate, or BMR, is the minimum number of calories or energy your body needs to perform vital functions like breathing, maintaining body temperature, and pumping blood.

As you lose weight with GLP-1s, your BMR may naturally decrease, as a smaller body usually needs fewer calories for sustenance. And because weight loss basically results from the difference between calories consumed and calories burned, and BMR makes up a large part of the calories you burn, a lower BMR can mean losing less weight. So this can be one reason why GLP-1s aren’t working as well for you.

You can learn more about how to speed up your metabolism, increase your BMR, and potentially tilt the scales in your favour here.

Metabolic age

Metabolic age is a comparison between your BMR and the average BMR of people in your age group. Basically, a lower metabolic age means that your body is running more efficiently than average, while a higher metabolic age means your metabolism is a bit slower than the average for your age.

Similarly to BMR, having a higher metabolic age, aka slower metabolism, can make weight loss a bit harder because your body burns fewer calories at rest.

Don’t think that it’s all doom and gloom, though. GLP-1s like Wegovy can also help your body age better by supporting your energy levels, mobility, and sleeping patterns.

Body composition

When you lose weight, not all of it comes from fat. Up to 40% can come from lean mass, which includes muscle, water, and organ tissue. This is really important because muscle is the body’s most metabolically active tissue. So having less muscle typically means lower BMR, which again can mean that GLP-1s are less effective (we’ve covered this in more detail earlier under Baseline metabolism).

Ways in which you can combat this and get better results with GLP-1s include increasing your protein intake to around 1.2–1.6 g per kilogram of body weight per day and doing resistance training.

Microbiome composition

Studies on twins show that less diverse bacteria in the gut microbiome can increase the risk of obesity. GLP-1 medications can change the composition and diversity of gut bacteria, suggesting that part of how these drugs work might involve beneficial shifts in your microbiome.

Some clinical evidence suggests that people who respond well to GLP‑1 therapy have different gut microbiomes compared with non‑responders. For example, liraglutide (a GLP-1 medication) was associated with an increase in beneficial bacteria like Lactobacillus, Bacteroides, and A. muciniphila, while other bacteria were more common in poorer responders.

This opens up the possibility that, in the future, we can develop strategies to improve the effectiveness of these medications by targeting specific changes in the microbiome itself through diet, prebiotics, or probiotics.

Hungry brain vs. hungry gut

This theory suggests that, due to differences in genetic makeup, people experience appetite differently. For some people, it’s driven more by cravings, and thus the neurological component is more dominant. These are the people who are more ‘hungry in the brain’. For others, the hunger signals originate more from the gut and are due to hormonal responses, so these people are more ‘hungry in the gut’.

People who are ‘hungry in the brain’ tend to eat very large meals, while those who are ‘hungry in the gut’ tend to snack more frequently, but usually eat normal portions.
A recent study has found that GLP-1s tended to work better for those with a ‘hungry gut’.

The biological ‘set point’ for weight

Scientists think there’s some sort of a biological ‘set point’, meaning a weight range your body defends as its preferred weight. So, for example, if you lose weight, your body will increase your hunger hormones and lower your BMR to push your weight back up towards the ‘set point’. This ‘set point’ can be influenced by many things, like genetics, hormones like leptin and ghrelin, and past weight history, and it can change throughout a person’s life.

This could explain at least in part why weight loss can cause your appetite to increase and metabolism to slow down after a period of weight loss, making it difficult to maintain your weight long-term.

Genetics and appetite, metabolism, and hormones

Genetics can influence your metabolism and hormone levels to affect how easily you lose or maintain weight and how you respond to weight loss medication:

Twin and family studies show a strong hereditary component to body weight and BMR, suggesting that genetics can cause some people to have an ‘energy-sparing’ metabolism that makes them prone to obesity.
Genetics also influence appetite‑regulating hormones like leptin and ghrelin, which regulate hunger, satiety, and energy balance, and therefore eating behaviour.

Genetics and drug metabolism

Many genes can influence your metabolism and overall response to weight-loss medications, but here are some of the main culprits science has uncovered so far:

GLP1R: This gene encodes the GLP-1 receptor, and variations in it have been linked to play a role in the response to GLP-1 receptor agonists.
TCF7L2: Variants in this gene can affect how the natural hormone GLP-1 works in the body, potentially altering how the body responds to GLP‑1 therapy (which mimics the natural hormone).
KCNJ11 and KCNQ1: They regulate insulin secretion and how hormones like GLP-1 work in the body. Variations in them have been linked to differences in response to diabetes medications like GLP-1s.