Tirzepatide (Mounjaro for type 2 diabetes, Zepbound for weight management) is a dual GIP/GLP-1 receptor agonist licensed in the UK that typically produces substantial weight loss rather than weight gain. Clinical trials demonstrate average reductions of 15–21% of baseline body weight over 72 weeks. However, some individuals may experience unexpected weight increases during treatment. Understanding why this occurs—whether due to medication adherence issues, concurrent medications, fluid retention, dietary factors, or normal physiological fluctuations—is essential for optimising outcomes. This article explores the reasons behind atypical weight gain on tirzepatide and provides practical guidance for patients and healthcare professionals.
Quick Answer: Weight gain on tirzepatide is uncommon, as clinical trials show average weight losses of 15–21%, but may occur due to medication non-adherence, concurrent weight-promoting drugs, fluid retention, dietary factors, or normal physiological fluctuations.
Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist licensed in the UK for the treatment of type 2 diabetes mellitus (as Mounjaro) and, more recently, for chronic weight management (as Zepbound) in adults with obesity or overweight with weight-related comorbidities. The medication is prescribed alongside a reduced-calorie diet and increased physical activity for weight management.
Clinical trial data consistently demonstrate that tirzepatide is associated with weight reduction rather than weight gain. In the SURMOUNT-1 trial, participants without diabetes receiving tirzepatide experienced average weight losses of approximately 15%, 19.5%, and 20.9% of their baseline body weight over 72 weeks, depending on the dose administered. Weight loss tends to be somewhat lower in people with type 2 diabetes, as demonstrated in the SURMOUNT-2 trial. These results represent significant weight reductions compared with many other pharmacological interventions for obesity.
The mechanism underlying tirzepatide's weight-reducing effects involves multiple pathways. The medication slows gastric emptying (an effect that may attenuate over time), which prolongs satiety after meals and reduces overall food intake. It also acts on appetite-regulating centres in the hypothalamus, decreasing hunger signals and food cravings. Additionally, tirzepatide influences glucose metabolism, which can contribute to changes in body composition.
Weight gain whilst taking tirzepatide is not expected on average, but individual responses vary. When patients report increasing weight during treatment, it is essential to explore alternative explanations, assess adherence to the medication regimen, and evaluate concurrent factors that may be influencing energy balance. Understanding the expected weight trajectory helps both patients and healthcare professionals approach unexpected weight changes systematically and identify any underlying issues requiring attention.
Although not expected, several factors may contribute to weight gain in individuals taking tirzepatide. Understanding these potential causes is crucial for appropriate management and optimising treatment outcomes.
Medication non-adherence or subtherapeutic dosing represents a possible explanation. Tirzepatide requires weekly subcutaneous injection, and missed doses or inconsistent administration can significantly reduce its effectiveness. Additionally, patients may still be in the dose-escalation phase, receiving a lower dose that has not yet achieved full therapeutic effect. The medication is typically initiated at 2.5 mg weekly and gradually increased, with several maintenance doses (5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg) used depending on response and tolerability. Weight loss generally becomes more pronounced at higher doses.
Concurrent medications may counteract tirzepatide's weight-reducing effects. Certain drugs are associated with weight gain, including some antipsychotics (olanzapine, quetiapine), mood stabilisers (sodium valproate, lithium), antidepressants (mirtazapine, some tricyclics), corticosteroids, insulin, sulfonylureas, and beta-blockers. If these medications have been recently initiated or dose-increased, they may offset tirzepatide's benefits. Note that insulin or sulfonylurea doses may need reduction when used with tirzepatide due to increased hypoglycaemia risk.
Fluid retention can manifest as apparent weight gain on the scales without representing true adipose tissue accumulation. Conditions such as heart failure, renal impairment, or venous insufficiency may cause oedema. Additionally, hormonal fluctuations during the menstrual cycle can lead to temporary fluid retention in premenopausal women.
Pregnancy is an important consideration in women of childbearing age. Tirzepatide is contraindicated in pregnancy, and weight gain could be an early sign of pregnancy. Effective contraception is essential during treatment.
Dietary and lifestyle factors remain fundamental to weight management. Increased caloric intake—whether from larger portion sizes, more frequent eating, or consumption of energy-dense foods—can counteract the appetite-suppressing effects of tirzepatide. Similarly, reduced physical activity due to illness, injury, or lifestyle changes decreases energy expenditure. Some patients may also experience 'compensatory eating', where they unconsciously increase food intake because they are taking a weight-loss medication, assuming it will offset dietary indiscretion.
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Start HereIf you experience weight gain whilst taking tirzepatide, a systematic approach can help identify the cause and guide appropriate management strategies.
Review your medication adherence first. Ensure you are administering your weekly injection consistently, at approximately the same time each week, and that you are storing the medication correctly (refrigerated at 2–8°C before first use; do not freeze). After first use, follow the specific storage instructions in the product information, which may allow limited room temperature storage. Check that you are using the correct dose as prescribed by your healthcare professional. If you have missed doses or are uncertain about your injection technique, contact your GP or practice nurse for guidance.
Keep a detailed food and activity diary for at least one week. Record everything you eat and drink, including portion sizes, snacks, and beverages. Note your physical activity levels and any changes to your usual routine. This information provides valuable insight into energy balance and can reveal patterns that may explain weight changes. Many patients find that mindful tracking alone helps them identify areas for improvement.
Assess for fluid retention by monitoring for signs such as swollen ankles, tight-fitting shoes or rings, or puffiness around the eyes. Weigh yourself at the same time each day (ideally first thing in the morning after emptying your bladder) to identify rapid fluctuations that suggest fluid rather than fat gain. True weight gain from increased adipose tissue typically occurs gradually over weeks, whereas fluid retention can cause several pounds of weight increase within days.
Schedule a review with your GP or prescribing clinician. They can evaluate potential contributing factors, including:
Review of all current medications for weight-affecting drugs
Assessment for underlying medical conditions (thyroid dysfunction, Cushing's syndrome, polycystic ovary syndrome)
Consideration of dose adjustment if you are not yet on an optimal maintenance dose
Evaluation for fluid retention or other medical causes
Pregnancy testing if appropriate
Seek urgent medical attention if you experience severe, persistent abdominal pain (which could indicate pancreatitis or gallbladder disease), persistent vomiting, yellowing of the skin or eyes, or sudden breathlessness with leg swelling. These symptoms require prompt assessment.
Women of childbearing age should note that tirzepatide may reduce the exposure of oral contraceptives, particularly during dose initiation or escalation. Consider using additional non-oral or barrier contraception for 4 weeks after starting treatment and after each dose increase. If you become pregnant, stop tirzepatide and seek medical advice promptly.
Do not discontinue tirzepatide without medical advice. Stopping the medication abruptly may lead to rebound weight gain and worsening of glycaemic control if you have type 2 diabetes. Your healthcare professional can help determine whether continuing, adjusting, or changing your treatment is most appropriate.
If you experience any suspected side effects from tirzepatide, report them to the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk).
Understanding that weight fluctuations are normal and that scale weight does not always reflect true changes in body composition is essential for patients taking tirzepatide.
Body composition changes may not be accurately reflected by scale weight alone. As patients increase physical activity—particularly resistance training—they may gain lean muscle mass whilst simultaneously losing fat mass. Since muscle is denser than adipose tissue, this favourable body composition change might result in stable or even slightly increased weight despite fat loss and improved metabolic health. Waist circumference, clothing fit, and body composition analysis (such as bioimpedance scales or DXA scans where clinically indicated) provide more comprehensive assessments than weight alone. Consider tracking your waist measurement monthly as a useful indicator of abdominal fat loss.
Normal weight fluctuations occur in all individuals, typically ranging from 1–2 kg day-to-day due to variations in hydration status, bowel content, dietary sodium intake, and hormonal influences. Women commonly experience cyclical weight changes of 1–3 kg related to the menstrual cycle, with fluid retention typically occurring in the luteal phase (the week before menstruation). These temporary fluctuations do not represent true fat gain and should not cause alarm.
Metabolic adaptation may occur during prolonged weight loss. As body weight decreases, basal metabolic rate naturally declines because there is less body mass to maintain. Additionally, the body may undergo adaptive thermogenesis—a reduction in energy expenditure beyond what would be predicted by weight loss alone. This physiological response can slow the rate of weight loss or, if caloric intake is not adjusted accordingly, potentially lead to weight stabilisation or modest regain. This does not indicate treatment failure but rather reflects normal metabolic regulation.
Gallstone formation can occur with rapid weight loss. If you experience upper abdominal pain, particularly after eating fatty foods, seek medical assessment as this could indicate gallbladder disease.
Psychological factors including stress, poor sleep quality, and emotional eating can influence weight independently of tirzepatide's pharmacological effects. Chronic stress elevates cortisol levels, which can promote central adiposity and increase appetite. Sleep deprivation disrupts appetite-regulating hormones (increasing ghrelin and decreasing leptin), leading to increased hunger and cravings for energy-dense foods.
Timing of weight assessment matters significantly. Weight loss with tirzepatide is not linear; patients typically experience more rapid initial weight reduction followed by a slower, steady decline. Plateaus lasting several weeks are common and do not indicate treatment failure. Long-term trends over months are more meaningful than week-to-week variations. If you have concerns about weight changes during tirzepatide treatment, discuss them with your healthcare professional, who can help interpret your individual response and optimise your treatment plan accordingly.
No, weight gain on tirzepatide is uncommon. Clinical trials consistently show average weight losses of 15–21% of baseline body weight over 72 weeks, making weight gain an unexpected response that warrants investigation.
Concurrent medications that may counteract tirzepatide's weight-reducing effects include antipsychotics (olanzapine, quetiapine), mood stabilisers (sodium valproate, lithium), certain antidepressants (mirtazapine), corticosteroids, insulin, sulfonylureas, and beta-blockers.
Contact your GP if weight gain persists despite good medication adherence and lifestyle measures, or seek urgent medical attention if you experience severe abdominal pain, persistent vomiting, jaundice, or sudden breathlessness with leg swelling.
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