- UK "non-response" rule: NICE says consider stopping if <5% of initial weight is lost after 6 months (semaglutide/Wegovy, TA875; for tirzepatide/Mounjaro, TA1026, this is measured after 6 months on the highest tolerated dose).
- Adherence dominates: real-world discontinuation of GLP-1 medicines runs at roughly 30–50% or more within a year — apparent non-response is more often stopping or missing doses than a true biological non-response.
- Genetics is real but small: the largest study to date found a GLP1R gene variant linked to about 0.76 kg extra weight loss per copy — a fraction of the total effect of the medicine.
- No genetic test is recommended: no UK, US or EU regulator advises genetic testing before prescribing, and no validated clinical test exists.
- Early progress predicts later progress: little weight change in the first few months is the practical early signal to review with your clinician.
What "not working" actually means
It helps to separate two different things people mean by a jab "not working":
- Clinical non-response — a measurable outcome. In the UK, NICE uses a clear threshold: if you have lost less than 5% of your starting weight after 6 months of treatment, your clinician should review whether continuing is worthwhile. This threshold appears in NICE's guidance for both semaglutide (Wegovy) and tirzepatide (Mounjaro).
- Biological non-response — the idea that your body simply doesn't respond to the drug at the receptor level. This is real for a small number of people, but it is much less common than the clinical picture suggests, because so many other things get in the way first.
In other words, many people labelled "non-responders" are really under-treated or under-dosed rather than genuinely immune to the medicine.
The biggest reasons a jab may not work
Before reaching for genetics, clinicians look at the far more common explanations — most of which can be addressed:
| Reason | What's going on |
|---|---|
| Not yet at the target dose | These medicines are increased gradually. Early on, or if the dose was never raised, you may simply not be on an effective dose yet. |
| Missed or skipped doses | Real-world use shows a large share of people stop or take doses irregularly within the first year, which blunts results. |
| Side effects limiting the dose | Nausea or gut symptoms can make it hard to reach a higher, more effective dose. |
| Diet and activity | The jabs work best alongside changes to eating and movement; they are not a standalone fix. |
| Other medicines or conditions | Some conditions and medications affect weight and can offset the benefit. |
| Expectations | Average trial weight loss is large, but individual results vary widely — "less than I hoped" is not the same as "no response". |
How much is genetics?
Your genes do influence how much you respond — but the effect is smaller than the headlines suggest. The largest study so far (a 2026 analysis of nearly 28,000 people who reported their results) found a common variant in the GLP1R gene — which codes for the receptor these drugs act on — associated with about 0.76 kg of extra weight loss for each copy of the helpful version. That is a genuine, statistically robust signal, but it is a small slice of the total weight change most people see.
Other genes have been linked to how much blood-sugar (HbA1c) improves in type 2 diabetes — for example a variant in the ARRB1 gene was the strongest such signal in one large study — but again the per-copy effect is modest. Across all the research, no single gene reliably decides who responds: the picture is polygenic (many small effects) and differs by drug, outcome and population. Taken together, the measurable genetic effect is well under a tenth of the drug's overall benefit.
Can I get a genetic test to find out?
Not in any way that would change your treatment. As of 2026, no medicines regulator — not the MHRA, the FDA or the EMA — recommends genetic testing before prescribing a GLP-1 medicine, and there is no validated clinical test that predicts response. Direct-to-consumer DNA services may report a GLP1R variant, but these are not clinical-grade and should not guide whether you start, stop or change a medicine. The reliable early signal is much simpler: your actual weight change over the first few months.
Are some people truly "non-responders"?
Yes — a small number of people do not respond well even when the dose is optimised and they are taking the medicine consistently. In type 2 diabetes, for example, there is some evidence that people whose bodies make very little of their own insulin (low C-peptide) tend to respond less to GLP-1 medicines, because these drugs partly work by helping the pancreas release insulin. But this is one factor among many, and it is something your diabetes team can consider — not something to self-diagnose.
What to do if your jab isn't working
The right next step is a conversation, not a workaround. Book time with your prescriber, GP or pharmacist and discuss:
- Whether you're at the right dose. If the dose was never increased to the target, that is often the single biggest lever.
- Side effects. If nausea is stopping you reaching a higher dose, there are ways to manage this — ask before you give up.
- Missed doses and supply. Gaps caused by shortages or forgetting can blunt results; a steady supply matters.
- Diet, activity and other medicines. A dietitian or your GP can help address the things working against the jab.
- Whether to switch or stop. If you've genuinely lost under 5% at 6 months on an optimised dose, NICE guidance supports reviewing whether to continue — a shared decision with your clinician.
Related reading
Mounjaro (tirzepatide) in the UK
Availability, price and how to access it.
Wegovy & Ozempic (semaglutide)
The difference and how to get them.
GLP-1 medicines and muscle loss
What the trials show and how to protect muscle.
Orforglipron: the oral GLP-1
Where the first weight-loss pill stands in the UK.
Mounjaro supply status
Live UK supply signals tracked by MediWatch.
Track your weight-loss medicine's supply
MediWatch checks official DHSC and NHS data daily and alerts you if your medication is affected.
Search shortages free →Official sources: NICE TA875 (semaglutide for obesity) · NICE TA1026 (tirzepatide for obesity) · NICE: reviewing and stopping tirzepatide · NHS: semaglutide · NHS: tirzepatide
Genetic evidence: GLP1R variant and GLP-1 response (Nature, 2026, PMID 41951734); ARRB1 pharmacogenetic signal (DIRECT GWAS, PMID 36528349); reduced GLP-1 response with low C-peptide (PMID 26802434). Genetic effects are modest and not yet clinically actionable; figures are approximate.
MediWatch is not medical advice. Always follow your prescription label and ask a pharmacist, GP, specialist, NHS 111, or emergency services if you are unsure or unwell.