Why Mounjaro or Wegovy Does Not Work for Everyone? What We Know So Far
“The Kitchen is your lab and food is your best medicine!”
~ Dr Nina
Mounjaro (tirzepatide) and Wegovy (semaglutide) can be incredibly helpful tools for some people, but they do not work equally well for everyone. That is not because one person is “trying harder” than another. It is because these medicines act on specific appetite, satiety, gastric-emptying and blood-sugar pathways, while obesity itself is biologically diverse. In other words, they target part of the problem, not every possible driver of weight gain [1].
I want to be very clear, there is nothing wrong with trying medication, and for many people it can reduce appetite, improve blood sugar control and support meaningful weight loss. But I also think it is important to remember how these medicines are actually described in official guidance: they are to be used together with diet and physical activity, not to replace the basics [2,3,4].
Those wording matters. Because when someone says, “Mounjaro isn’t working for me,” or “Wegovy is barely doing anything,” my first thought is not that they have failed. My first thought is that we need to ask better questions. Is this the wrong tool for their biology? Are they a slow responder rather than a non-responder? Have they reached an effective dose? Have they implemented all foundations - food, blood sugar balance, movement, sleep, stress and long-term habits.
One of the clearest things the research shows is that these drugs do not work equally for everyone. In a 2025 BMJ Open real-world cohort of 483 adults treated with GLP-1 analogue therapy for obesity, 17.8% were classed as non-responders, 48.4% as moderate responders and 33.8% as hyper-responders [5]. That is a huge spread. It tells us that even within the same drug class, people respond very differently. A separate phenotype-based obesity study also supports the idea that obesity is not one single condition. Some people are more “hungry brain”, some more “hungry gut”, some more “emotional hunger”, and some more “slow burn”, which helps explain why one approach can feel life-changing for one person and disappointing for another [6]. Therefore, choosing anti-obesity interventions/medication according to phenotype produced substantially more weight loss than a non-phenotype-guided approach.
From a nutritional therapy perspective, that makes complete sense. If the main driver of someone’s weight is severe insulin resistance, chaotic eating patterns, ultra-processed food reliance, poor sleep, stress-driven eating, low protein intake, low muscle mass, or emotional coping through food, then a gut-hormone medication may help with appetite, but it may not fully address the real reason they are stuck. And if the basics are not in place, the medication may end up doing less than people hoped. That does not mean the drug is useless. It means weight regulation is more complicated than a prescription alone.
Insulin resistance and type 2 diabetes seem to make response slower
One of the most consistent patterns in the literature is that people with type 2 diabetes tend to lose less weight on these medicines, on average, than people without diabetes. In STEP 1, adults with overweight or obesity without diabetes lost a mean 14.9% of body weight with semaglutide 2.4 mg over 68 weeks [7]. In STEP 2, adults with overweight or obesity with type 2 diabetes lost 9.6% [8]. A similar pattern appears with tirzepatide: in SURMOUNT-1, adults without diabetes lost 19.5% and 20.9% at 10 mg and 15 mg for 72 weeks [9], whereas in SURMOUNT-2, adults with obesity and type 2 diabetes lost 12.8% and 14.7% at 10 mg and 15 mg for 72 weeks [10].
I think this is where the conversation around insulin resistance becomes very important. The trials show the pattern clearly, even if they do not prove that insulin resistance is the only explanation. People with type 2 diabetes often come with a different metabolic background, different medications, different appetite signalling, and often a longer history of weight dysregulation. So if someone with diabetes loses more slowly on Wegovy or Mounjaro, that is not necessarily a sign the drug is “failing.” But it may be a sign that food quality, meal structure, blood sugar stability, muscle-preserving movement and wider metabolic support need even more attention.
Sex differences are real, but they do not explain everything
A 2026 systematic review and meta-analysis in JAMA Internal Medicine found that GLP-1 receptor agonists produced greater weight loss in women than in men. Importantly, the same review did not find clear differences by age, race and ethnicity, baseline BMI or baseline HbA1c [11]. The BMJ Open real-world study also found that female sex was associated with hyper-response, while age, baseline BMI and diabetes status were not independent predictors [12]. So sex seems to matter, but many of the other obvious things people assume should predict response - such as starting weight - do not seem to provide any explanation.
Genetics, leptin and hormone signalling probably matter too — but we are not yet at the point of easy prediction
This is one of the most interesting areas, but also one of the messiest. A large pharmacogenomic study found that certain variants, especially in ARRB1, were associated with differences in glycaemic response to GLP-1 receptor agonists [13]. But this does not yet translate into a simple clinical test that can tell us who will or will not lose weight on Wegovy or Mounjaro. A 2025 study looking at two GLP1R variants, rs6923761 and rs761387, in people taking oral semaglutide also found no significant association with changes in HbA1c, BMI or blood pressure [14]. So, genetics may matter, but we do not have enough data yet.
Leptin
Leptin is another fascinating piece of the puzzle. Leptin is central to hunger, satiety and energy balance, and it almost certainly matters in obesity biology. A 2025 semaglutide study found significant reductions in insulin and leptin levels after 12 weeks, and a meta-analysis reported beneficial effects of tirzepatide on leptin and adiponectin levels in people with type 2 diabetes [15]. That tells us these medicines do interact with adipose-hormone signalling. For tirzepatide, the leptin story is even more intriguing. Research [16, 17] suggests that tirzepatide may improve leptin sensitivity, and that baseline circulating leptin correlates with weight-loss efficacy. But we cannot yet say, with confidence, that baseline leptin testing can predict who will respond well in day-to-day clinical practice.
Sometimes the issue is not biology alone – dose, titration and tolerability
This is a huge point, and one that gets missed all the time. In a 2025 real-world titration study, only 52.9% of semaglutide users reached the recommended 2.4 mg maintenance dose, compared with 77.6% of tirzepatide users reaching 15 mg. Semaglutide users also took much longer to get there in this study [18]. So, when someone says the medication did not work, part of the story may simply be that they never reached an effective dose for long enough. This could be due to extreme side effects or simply money constrains.
There is also the issue of “slow responders”. A post hoc analysis of SURMOUNT-1 found that among people who had not lost 5% of body weight by week 12, 90% still went on to achieve at least 5% weight loss by week 72 [19]. The mean time for these later responders to reach that threshold was about 24.8 weeks. So, a slow start does not automatically mean the drug will not work. Sometimes the biology is just slower. However, I would argue if you would like to stay on the drug for such a prolong period with such a small weigh loss. I suppose everything needs to be personalised.
That said, there comes a point where it is reasonable to step back and ask whether the treatment is a good fit. NICE advises that if someone has lost less than 5% of their initial weight after 6 months on the highest tolerated dose of tirzepatide, the clinician and patient should discuss why weight loss has been less than desired and decide whether continuing treatment makes sense, while remembering that people with type 2 diabetes may lose weight more slowly [21]. I think that is a very sensible and humane approach.
Why I still come back to the basics
This is the part I feel most strongly about.
On average, these newer medications often produce more weight loss than standard lifestyle advice alone in clinical trials. We should be honest about that. But that is not the same as saying diet and lifestyle are second best, or that they are somehow optional. Intensive lifestyle interventions can still produce clinically meaningful weight loss and major metabolic improvements. In the Look AHEAD trial, intensive lifestyle intervention produced 8.6% weight loss at one year and improved fitness, glycaemic control and cardiovascular risk factors [22,23]. In the DiRECT trial, a structured weight-management programme delivered in primary care produced a mean 10.0 kg weight loss at 12 months, and 46% of participants achieved remission of type 2 diabetes [24].
That is why I do not see this as a competition between “natural” approaches and medication. I see it as a question of matching the right tool to the right person, at the right time. For some people, Mounjaro or Wegovy may be the tool that finally helps them get traction. For others, the better place to start may be the basics: stabilising meals, reducing ultra-processed foods, improving sleep, building movement, supporting muscle mass, and calming the blood sugar rollercoaster. And for many people, the best results may come from doing both together.
In fact, the SURMOUNT-3 trial is a lovely reminder that lifestyle intervention is not powerless. Participants first completed a 12-week intensive lifestyle programme and lost an average of 6.9% of body weight before tirzepatide was added. The cumulative 24.3% reduction came from lifestyle intervention followed by medication, not medication in isolation [25].
Another reason I believe the basics matter is maintenance. In the STEP 1 extension, people regained much of the lost weight after semaglutide was stopped, and cardiometabolic improvements drifted back toward baseline [26]. In the STEP 4 withdrawal trial, people who continued semaglutide kept losing weight, while those switched to placebo regained weight despite lifestyle intervention [27]. None of this means the drugs are bad. It means obesity is chronic, biology pushes back, and long-term habits still matter enormously whether you use medication or not.
Final Thoughts
My view is simple. There is absolutely nothing wrong with trying Mounjaro or Wegovy. For the right person, they can be excellent tools. But if they are not working, or are working very slowly, I do not think the right conclusion is “I am broken.” Sometimes it means type 2 diabetes or other metabolic factors are slowing the response. Sometimes it means the dose or time frame has not been right. And sometimes it means the foundations need attention first.
As a nutritional therapist, I would much rather ask: “what does this person actually need?” More medication? More time? Better blood sugar balance? Better meals? Better sleep? More muscle? Less stress? A more personalised plan? Because in the end, the goal is not simply to be on a drug that works on paper. The goal is to find an approach that works for the person in real life — with or without medication.
So yes, hormones matter. Genetics matters. Appetite signalling matters. But this is exactly why I prefer a personalised, whole-person approach rather than a one-size-fits-all assumption that everyone should respond the same way to the same weekly injection.
References
1. Tirzepatide Once Weekly for the Treatment of Obesity
2. Wegovy | European Medicines Agency (EMA)
3. 1 Recommendations | Semaglutide for managing overweight and obesity | Guidance | NICE
4. 1 Recommendations | Tirzepatide for managing overweight and obesity | Guidance | NICE
7. Once-Weekly Semaglutide in Adults with Overweight or Obesity
9. Tirzepatide Once Weekly for the Treatment of Obesity
10.Tirzepatide_once_weekly_for_the_treatment_of_obesity_in_people_with_type_2_diabetes.pdf
22. Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes
