Feeling cold on retatrutide is a side effect reported by some participants in clinical trials of this investigational triple receptor agonist. Retatrutide targets GLP-1, GIP, and glucagon receptors simultaneously and is not yet licensed in the UK. Cold sensations during treatment are most likely linked to rapid weight loss and reduced caloric intake, both of which affect the body's ability to retain and generate heat. This article explains why this occurs, how common it may be, when to seek medical advice, and practical strategies to manage cold sensations safely whilst participating in a retatrutide clinical trial.

Why Retatrutide May Cause You to Feel Cold

Feeling cold on retatrutide is most plausibly caused by loss of insulating adipose tissue and reduced caloric intake driving adaptive thermogenesis, rather than a direct pharmacological effect on temperature regulation.

Retatrutide is an investigational triple receptor agonist that targets the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors simultaneously. It is not licensed in the UK and is currently available only through clinical trials. This multi-receptor activity drives significant reductions in appetite, caloric intake, and body weight — effects that, while therapeutically promising, can also influence how the body regulates temperature.

Feeling cold during retatrutide treatment is most plausibly linked to rapid or substantial weight loss and reduced caloric intake, rather than a direct pharmacological effect on thermoregulation. Adipose (fat) tissue plays an important role in insulation and heat retention. As body fat decreases, some individuals notice they feel colder than usual, particularly in the hands, feet, and extremities. This is consistent with research on adaptive thermogenesis — the well-recognised reduction in heat production that accompanies calorie restriction and weight loss more broadly — and is not unique to retatrutide.

The glucagon receptor component of retatrutide may influence energy expenditure and thermogenesis based on preclinical and physiological studies, but the clinical relevance of this effect on perceived body temperature in humans remains under investigation and should not be overstated.

It is also worth considering whether nutritional deficiencies — which can develop during periods of significant dietary restriction — may contribute to cold sensations. Iron deficiency anaemia, in particular, is associated with feeling cold (NHS). If you are experiencing persistent cold feelings during treatment, it is important to discuss this with your GP or study clinician to ensure your nutritional intake remains adequate.

Important: Retatrutide is investigational and unlicensed in the UK. It should only be taken as part of an approved clinical trial. Do not attempt to obtain it from unregulated sources.

How Common Is This Side Effect in Clinical Trials?

Precise incidence figures for cold sensations are not available from published Phase 2 data; the most commonly reported adverse events in trials were gastrointestinal, including nausea, vomiting, and diarrhoea.

Retatrutide is not approved by the Medicines and Healthcare products Regulatory Agency (MHRA) or the European Medicines Agency (EMA) and remains under clinical investigation. The most significant published data come from a Phase 2 trial published in The New England Journal of Medicine (Jastreboff et al., 2023), which evaluated retatrutide across multiple doses in adults with obesity or overweight.

Whilst cold sensations were reported by some participants in that trial, precise incidence figures for 'feeling cold' as a discrete adverse event are not available in the published data, and robust population-level frequency data have not yet been established. Any claims about how commonly this symptom occurs — or how it varies by dose or degree of weight loss — cannot be confirmed from currently available evidence and should be treated with caution.

The most commonly reported adverse events in the Phase 2 trial were gastrointestinal in nature — including nausea, vomiting, diarrhoea, and constipation — consistent with the GLP-1 receptor agonist class.

For context, cold sensations have been reported anecdotally by some users of approved GLP-1-based therapies such as semaglutide (Wegovy, Ozempic); however, 'feeling cold' is not listed as a recognised adverse reaction in the UK Summary of Product Characteristics (SmPC) for semaglutide and should therefore be regarded as patient-reported rather than regulator-confirmed for this drug class. Whether retatrutide will carry a similar or different pattern of cold-related symptoms will only become clear once Phase 3 trial data and regulatory review are complete.

Regulatory agencies such as the MHRA require full Phase 3 data before a side effect profile is formally characterised in a SmPC. Patients should be reassured that cold sensations, where they do occur, have generally been described as mild in the context of weight-loss therapies.

When to Seek Medical Advice About Feeling Cold

Seek medical advice if cold sensations are persistent or accompanied by fatigue, pallor, hair loss, or discoloured fingers and toes, as these may indicate anaemia, thyroid dysfunction, or Raynaud's phenomenon.

Whilst mild cold sensations during retatrutide treatment are generally not a cause for alarm, there are specific circumstances in which you should seek medical advice.

Contact your GP, prescribing clinician, or clinical trial team if:

• Cold feelings are persistent, worsening, or significantly affecting your quality of life

• You notice cold sensations accompanied by unusual fatigue, pallor, shortness of breath, or dizziness, which may suggest anaemia — your GP can arrange a Full Blood Count (FBC) and ferritin level to investigate

• You experience cold, numb, or discoloured fingers and toes (particularly white, blue, or red colour changes), which could indicate Raynaud's phenomenon — a condition affecting blood flow to the extremities (NHS)

• You have unexplained hair loss alongside cold intolerance, which may point to thyroid dysfunction — a Thyroid Function Test (TFT) can be arranged by your GP

• Cold feelings develop alongside significant muscle weakness or cramps, which could suggest an electrolyte imbalance — your GP can arrange Urea and Electrolytes (U&Es) and other relevant blood tests

• You experience persistent vomiting, diarrhoea, or an inability to keep fluids down, as these can lead to dehydration and, in some cases, acute kidney injury (AKI) — seek prompt medical review if you notice reduced urine output or feel faint

If you are enrolled in a clinical trial, contact your study team before making any changes to your treatment or if you develop new or worsening symptoms.

Call 999 or attend your nearest A&E immediately if you feel extremely cold alongside chest pain, confusion, slurred speech, or loss of consciousness, as these may indicate a serious medical event requiring urgent attention.

Call NHS 111 if you need urgent medical advice but your symptoms are not immediately life-threatening.

Hypothyroidism (underactive thyroid) is a common cause of cold intolerance in the general population and should be excluded if symptoms are persistent (NHS). Never stop taking retatrutide without first discussing it with your prescribing clinician or study team.

Managing Cold Sensations During Treatment

Layering clothing, maintaining adequate iron and B12 intake, and staying physically active can help manage cold sensations; any dose adjustments must be agreed with the clinical trial team.

For most people, feeling cold on retatrutide is a mild experience that can be managed with some practical adjustments. The following strategies may help reduce discomfort whilst continuing treatment.

Practical measures to stay warm:

• Layer clothing, particularly thermal base layers, to retain body heat

• Wear warm socks and gloves, especially in cooler environments or during winter months

• Use heated blankets or hot water bottles when resting — take care to avoid burns, particularly if you have reduced sensation in your hands or feet

• Keep your home at a comfortable, consistent temperature

Nutritional support is equally important. Ensuring adequate intake of iron-rich foods (such as lean red meat, lentils, spinach, and fortified cereals) and vitamin B12 (found in meat, dairy, and eggs) can help prevent deficiencies that may worsen cold sensations. If your dietary intake is restricted due to appetite suppression, discuss this with your clinician or a registered dietitian before starting any supplements. It is advisable to check relevant blood tests — including FBC, ferritin, B12, and folate — before supplementing, to ensure treatment is appropriate and targeted (NICE CKS).

Staying physically active — even with gentle exercise such as walking — can help maintain metabolic rate and improve circulation, both of which support normal body temperature regulation. Exercise also helps preserve lean muscle mass during weight loss, which is metabolically active tissue that contributes to heat production.

If cold sensations are particularly bothersome, your clinician or study team may consider adjusting the dose escalation schedule — a common approach with GLP-1-based therapies where tolerability issues arise. Because retatrutide is investigational, any changes to your dosing regimen must follow the clinical trial protocol and be agreed with your study team. Do not adjust your dose independently.

Other Side Effects to Be Aware of With Retatrutide

The most common retatrutide side effects are gastrointestinal, including nausea, vomiting, and diarrhoea; serious risks include pancreatitis, gallbladder disease, and increased heart rate requiring prompt medical attention.

Beyond feeling cold, retatrutide is associated with a broader range of side effects, the majority of which relate to its gastrointestinal activity via GLP-1 receptor agonism. Being aware of these can help you manage your treatment more effectively and know when to seek support.

Common gastrointestinal side effects include:

• Nausea — the most frequently reported side effect, particularly during dose escalation

• Vomiting — often linked to nausea and typically dose-dependent

• Diarrhoea and constipation — both have been reported, reflecting altered gut motility

• Decreased appetite — a desired therapeutic effect, but one that requires monitoring to ensure adequate nutrition

Severe or prolonged vomiting and diarrhoea can lead to dehydration and, in some cases, acute kidney injury (AKI). Ensure you maintain adequate fluid intake. If you are unable to keep fluids down, contact your study team, GP, or NHS 111 promptly.

Other reported or anticipated side effects based on Phase 2 data and the known pharmacology of the drug class include:

• Injection site reactions — redness, bruising, or mild discomfort at the site of subcutaneous injection

• Fatigue — commonly associated with caloric restriction and rapid weight loss

• Headache — reported with GLP-1 receptor agonists as a class

• Increased heart rate (tachycardia) — a known class effect of GLP-1 receptor agonists; your clinician may monitor your pulse during treatment

Gallbladder disease, including gallstones (cholelithiasis) and gallbladder inflammation (cholecystitis), is a recognised risk with GLP-1 receptor agonists and with rapid weight loss more broadly. Seek prompt medical attention if you develop pain in the upper right abdomen, fever, or yellowing of the skin or eyes (jaundice) (NHS).

Pancreatitis is a rare but serious risk associated with GLP-1 receptor agonists. Seek urgent medical attention — call 999 or attend A&E — if you develop severe, persistent abdominal pain, particularly if it radiates to the back (NHS).

Hypoglycaemia (low blood sugar): If you are also taking insulin or a sulfonylurea (e.g., gliclazide) for diabetes, your risk of hypoglycaemia may be increased. Your clinician should review your diabetes medications when starting retatrutide, and you should monitor your blood glucose as advised.

Thyroid considerations: Animal studies have identified C-cell tumours of the thyroid with GLP-1 receptor agonists; the relevance of this finding to humans is currently unknown and has not been confirmed by regulatory bodies. As a precaution, seek medical advice if you notice a lump or swelling in your neck, difficulty swallowing, or persistent hoarseness.

Pregnancy and breastfeeding: Weight-loss pharmacotherapy is not recommended during pregnancy. Clinical trials exclude pregnant and breastfeeding individuals. If you become pregnant whilst taking retatrutide, stop the study drug and contact your study team and GP urgently.

Reporting side effects: If you experience a suspected side effect from retatrutide, please report it via the MHRA Yellow Card Scheme (available at yellowcard.mhra.gov.uk). Reporting helps build the safety evidence base for investigational medicines.

As retatrutide continues through clinical development, its full side effect profile will become clearer. Always report any new or worsening symptoms to your healthcare provider or study team promptly.

Frequently Asked Questions