Feeling Cold on Retatrutide: Causes and Safety

Feeling cold on retatrutide is a symptom reported by some participants in clinical trials of this investigational triple receptor agonist, developed by Eli Lilly. Retatrutide has no marketing authorisation in the UK or elsewhere and is available only within authorised clinical trials. Cold intolerance during significant weight loss is a recognised physiological response and is not unique to any single medicine. This article explains the possible mechanisms behind this symptom, what the current trial data show about retatrutide's side effect profile, when cold intolerance warrants medical attention, and the limitations of the evidence available so far.

What is retatrutide and what is its regulatory status in the UK?

Retatrutide is an investigational triple agonist (GLP-1, GIP and glucagon receptors) with no UK marketing authorisation; it is available only within authorised clinical trials and has not been assessed by the MHRA for safety, quality or efficacy outside that setting.

Retatrutide holds no marketing authorisation in the UK or anywhere else, and it can be obtained only within an authorised clinical trial.^[4][8] It is an investigational medicine developed by Eli Lilly that acts simultaneously on three hormone receptors: the glucagon-like peptide-1 (GLP-1) receptor, the glucose-dependent insulinotropic polypeptide (GIP) receptor, and the glucagon receptor.^[1][2] This triple agonist mechanism distinguishes it pharmacologically from currently authorised GLP-1 and dual GIP/GLP-1 receptor agonists, though no head-to-head trials have compared it directly with licensed treatments.

Because retatrutide has no UK marketing authorisation, the MHRA has not assessed it for safety, quality or efficacy outside the trial setting. It cannot be advertised, and anything sold online as retatrutide is not a licensed product and may be falsified. People interested in licensed weight-management treatments can discuss the options available to them with their GP.

The clinical trial programme for retatrutide includes the TRIUMPH and TRANSCEND series of studies.^[14] Phase 2 data published in the New England Journal of Medicine provided early findings in adults with obesity. Phase 3 results from these programmes have begun to emerge, including some congress presentations and press releases, though peer-reviewed publication and regulatory review by bodies such as the MHRA and the European Medicines Agency (EMA) have not yet been completed. All findings discussed in this article relate specifically to those trial populations and cannot be generalised as predictions of individual outcomes.

Why might people report feeling cold during clinical trials?

Feeling cold during retatrutide trials most likely reflects reduced metabolic rate and peripheral blood flow redistribution caused by rapid weight loss and lower caloric intake, rather than a confirmed direct pharmacological effect of the medicine.

Feeling cold is a recognised physiological response to rapid changes in body weight and energy metabolism, and this is the most plausible explanation for cold sensation reported during significant weight loss, including in weight-management trials. When caloric intake falls substantially and body fat is lost at an accelerated rate, the body's resting metabolic rate can decrease and peripheral blood flow may be redistributed, both of which can produce a subjective sense of feeling cold. This phenomenon is not unique to any single medicine and has been observed with other agents that produce significant weight reduction.

The glucagon receptor component of retatrutide's mechanism may also be relevant. Glucagon is thought to play a role in thermogenesis and energy expenditure in animal models, and modulating glucagon signalling could in principle influence how the body generates and conserves heat.^[13] However, the precise contribution of each receptor pathway to thermal regulation in humans is not yet established, and this remains a hypothesis rather than a confirmed mechanism.

Reduced food intake itself can lower core body temperature independently of any pharmacological effect. Participants in weight-management trials often report feeling cold as a secondary consequence of eating less. Distinguishing between these mechanisms requires careful trial design, and the available data do not yet allow a definitive conclusion about whether cold sensation in retatrutide trials reflects a direct drug effect, a consequence of weight loss, or a combination of both.

Other causes of persistent cold intolerance should also be considered. Hypothyroidism, iron-deficiency anaemia, and Raynaud's phenomenon can all produce a feeling of being cold and are unrelated to trial participation.^[12] If cold intolerance is persistent, distressing, or accompanied by other symptoms, a GP can assess whether one of these conditions requires investigation.

What side effects have been recorded in retatrutide trials so far?

The most commonly recorded adverse effects in retatrutide trials are gastrointestinal, including nausea, vomiting, diarrhoea and constipation; increases in heart rate and injection-site reactions have also been reported. Feeling cold is not a prespecified adverse event in published Phase 2 data.

The most commonly reported adverse effects in retatrutide trials to date have been gastrointestinal in nature, including nausea, vomiting, diarrhoea and constipation, consistent with the GLP-1 receptor agonist component of the drug's mechanism. These effects were generally reported as mild to moderate in severity and were more frequent during dose escalation phases, according to Phase 2 trial findings published in the New England Journal of Medicine in adults with obesity.

Injection-site reactions have also been recorded, as have increases in heart rate, which is a recognised effect of GLP-1 receptor agonism, as reported in the Phase 2 obesity trial. The glucagon receptor component introduces additional metabolic considerations, and researchers have monitored participants for effects on blood glucose, liver enzymes and lipid profiles. Hypoglycaemia was observed more frequently when retatrutide was used alongside other glucose-lowering agents, as noted in Phase 2 data from participants with type 2 diabetes.^[5]

Cold intolerance or feeling cold has not been characterised as a prespecified adverse event in published Phase 2 data, and no primary source documents it as a confirmed drug-specific effect. It is mentioned in this article as a symptom that may arise during rapid weight loss rather than as an established pharmacological consequence of retatrutide. As with all investigational medicines, the full safety profile will only become clearer as Phase 3 trial data from the TRIUMPH and TRANSCEND programmes are fully reported and reviewed by regulators.

Anyone participating in an authorised retatrutide clinical trial who experiences side effects should report them to the trial team under the study protocol in the first instance. Suspected adverse reactions can also be reported to the MHRA via the Yellow Card scheme at yellowcard.mhra.gov.uk.

When should you be concerned about feeling cold or other symptoms?

Cold intolerance accompanied by fatigue, dry skin, pallor or colour changes in the fingers and toes warrants GP assessment to exclude thyroid, anaemia or vascular conditions. Severe abdominal pain, signs of allergic reaction, or chest pain require immediate emergency care.

Feeling cold during a period of significant weight loss is usually a benign and temporary symptom, but certain accompanying features warrant prompt medical attention. If cold sensation is accompanied by persistent fatigue, unexplained weight gain, dry skin, constipation or a slowed heart rate, these may suggest an underlying thyroid abnormality that should be assessed by a GP rather than attributed to the trial medicine without investigation. Persistent cold intolerance alongside pallor, breathlessness on exertion or unusual tiredness may point to iron-deficiency anaemia and similarly warrants a GP review. Cold fingers and toes that change colour in response to cold or stress may suggest Raynaud's phenomenon, which a GP can assess and advise on.

Participants in retatrutide trials should follow the escalation pathways set out in their trial protocol, as the trial team is best placed to assess whether a symptom is related to the investigational medicine, requires dose adjustment, or needs independent clinical evaluation. If you need emergency care, tell the clinicians that you are participating in a clinical trial and show your trial identification card so that they are aware of the investigational medicine you are receiving.

More urgent symptoms that require immediate assessment include severe abdominal pain, which may indicate pancreatitis, a condition that has been reported with GLP-1 receptor agonist class medicines.^[6] Signs of a serious allergic reaction, including widespread rash, difficulty breathing or significant facial swelling, require emergency services (999) without delay. Chest pain, severe breathlessness, fainting or collapse also require an immediate 999 call or attendance at an accident and emergency department. Palpitations without any of these accompanying features are generally better assessed via NHS 111 or an urgent GP appointment rather than by calling 999.

For non-emergency concerns that cannot wait for a routine GP appointment, NHS 111 can provide advice. Participants in clinical trials should always contact their trial team in the first instance for symptoms that may be related to the study medicine.

If you are a trial participant, speak to your trial team about any requirements relating to pregnancy, breastfeeding or contraception, as clinical trial protocols typically include specific guidance on these matters that must be followed throughout your participation.

What are the limitations of the current trial data on retatrutide?

Current evidence is limited to Phase 2 data from small, specific populations and emerging Phase 3 results not yet fully peer-reviewed; no regulatory body has completed a marketing authorisation review, so no approved safety label, NICE guidance or long-term outcome data exist.

The current evidence base for retatrutide is still developing, and several important limitations apply to the data published so far. Phase 2 trial findings, while informative, involved relatively small numbers of participants over a limited duration, and they were conducted in specific populations that may not reflect the full range of people who might eventually be eligible for such a treatment. Phase 3 data from the TRIUMPH and TRANSCEND programmes have begun to emerge through congress presentations and press releases, but peer-reviewed publication of these results is ongoing and regulatory review by bodies such as the MHRA and the EMA has not yet been completed.

Because retatrutide has not been assessed by a regulator for a marketing authorisation, there is no approved Summary of Product Characteristics (SmPC) setting out its contraindications, warnings or recommended use. This means that safety signals identified in trials, including any association with feeling cold, have not been formally characterised or placed in clinical context by a regulatory body. The absence of an authorised label also means that guidance from NICE on its use within the NHS does not exist.

Long-term safety data are limited. The effects of sustained triple receptor agonism on cardiovascular outcomes, renal function and other organ systems over years rather than months are not yet established. Subgroup analyses for people with pre-existing conditions, including those with pre-existing diabetic eye disease, where rapid glycaemic improvement may transiently worsen pre-proliferative or proliferative retinopathy, require further investigation. Until regulatory review is complete and a marketing authorisation is granted, retatrutide remains an investigational medicine and no timeline for authorisation can be given.

Scientific References

1. Triple–Hormone-Receptor Agonist Retatrutide for Obesity (Jastreboff et al.).
2. Triple-Hormone-Receptor Agonist Retatrutide for Obesity (Jastreboff et al., PubMed abstract).
3. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, for people with type 2 diabetes (Bajaj et al.).
4. Retatrutide showing promise in obesity (and type 2 diabetes) (Doggrell).
5. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: phase 2 trial.
6. GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists: strengthened warnings on acute pancreatitis.
7. The Yellow Card scheme: guidance for healthcare professionals, patients and the public.
8. Medicines for human use under evaluation – European Medicines Agency.
9. Worsening of diabetic retinopathy with rapid improvement in glycaemic control (Bain et al.).
10. Early Worsening of Diabetic Retinopathy in the DCCT.
11. Involvement of basal metabolic rate in determination of cold tolerance phenotype (Maeda et al.).
12. Raynaud's – NHS.uk.
13. GLP-1 Is Not Enough: Can Glucagon Fill the Energy Expenditure Gap?.
14. Retatrutide for the treatment of obesity, obstructive sleep apnoea and osteoarthritis – TRIUMPH programme overview (Giblin et al.).

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