How GLP-1s work in the body 

Glucagon-Like Peptide-1 (GLP-1) is a hormone produced and secreted by the intestinal epithelial endocrine L-cells, by the differential processing of its precursor proglucagon. The physiology of GLP-1 begins with its release upon meal intake, and its primary actions are to stimulate insulin secretion and inhibit gastrointestinal motility and secretion. Recent pharmacological studies have also revealed that it can act as a physiological regulator of appetite, controlling food intake.¹ A reduction in GLP-1 secretion has been linked to the development of obesity. Current research aims to use GLP-1 and its associated pathways to reduce obesity and potentially manage and treat type 2 diabetes.¹

The appetite-suppressing and weight-reducing effects of GLP-1 are evolutionarily conserved in both animals and humans, underscoring its central role in energy balance.² A comprehensive review of randomised controlled trials evaluating several GLP-1 agonists further reinforces their therapeutic potential.³ Interestingly, these trials revealed that while GLP-1 levels were often not directly correlated with insulin concentrations or insulin resistance markers, the mechanisms remain multifactorial and more evidence from real-life, long-term studies to evaluate the true clinical efficacy and safety. Safety should be taken to follow national and international guidelines and recommendations before GLP-1 medication, or GLP-1 agonists, or substances that mimic the function of the GLP-1 molecule is prescribed.⁴

According to the Medicines and Healthcare Products Regulatory Agency (MHRA), the side effects of GLP-1 receptor agonists, with active ingredients including exenatide, lixisenatide, liraglutide, dulaglutide, semaglutide and tirzepatide, should be made aware to patients to ensure safety.⁵ These medicines work by mimicking the action of the natural hormone GLP-1, which helps regulate blood sugar levels by stimulating insulin secretion, reducing glucagon secretion, slowing gastric emptying, and promoting satiety.⁵

GLP-1 agonist side effects that can hinder treatment adherence  

However, treatment adherence can be hindered by gastrointestinal effects, which can limit the maximal efficacy of GLP-1 therapeutics, due to patient compliance.⁶ Interestingly, the co-administration of other molecules such as glucose-dependent insulinotropic polypeptide receptor (GIPR) has shown promise in reducing these side effects, particularly vomiting.⁶ 

Gastrointestinal symptoms, such as constipation, diarrhoea, bloating, and gas, are also associated with delayed gastric emptying and altered gut motility. These effects are the physiological actions of GLP-1 on the digestive system, which explain their prevalence among users of GLP-1 agonists.⁷

An expert panel, comprising endocrinologists, nephrologists, primary care physicians, and other healthcare professionals, provided practical recommendations to mitigate these side effects.⁸ Their guidance includes consuming bland, dry foods such as crackers, apples, and ginger-based drinks 30 minutes after GLP-1 receptor agonist treatment to minimise the occurrence or severity of nausea. Moreover, in case of vomiting and diarrhoea, adequate hydration is essential. 

One of the most important things to do when taking GLP-1 agonist medications is to monitor the occurrence of symptoms and identify triggers, as well as when to seek help. For example, depending on the frequency and severity, diet adjustments may be necessary to alleviate symptoms. However, this is something that would need to be discussed with your GP, because symptoms can also be a sign that the treatment dose is too high or that the treatment increment is occurring faster than your body can cope with. Moreover, individual gut sensitivities should also be taken into consideration, as these may change the perception of symptoms. However, if symptoms persist or you are worried about them, it is always good to follow the medical advice, as symptoms could indicate something more serious, such as gallbladder issues an area that continues to be studied.^9,10

Ultimately, GLP-1 agonists represent a foundational therapy in the evolving field of other gut hormone-based obesity and type 2 diabetes treatments. As more pharmacotherapies with varied mechanisms become available, clinicians will be able to tailor treatment plans based on individual conditions and the specific purpose of each medication. This would support patients to achieve their long-term goals and improve their quality of life.¹¹ 

When to talk to your doctor 

While GLP-1 receptor agonists can be highly effective in managing conditions such as type 2 diabetes and obesity, it is essential to be aware of certain red flags that may indicate the need for medical intervention. Persistent vomiting, severe abdominal pain, and signs of dehydration, which include excessive thirst, dizziness, or dark-coloured urine, are all warning signs that should not be ignored. These symptoms may suggest that the body is reacting poorly to the medication, and timely medical advice is necessary to prevent further complications. In such cases, it may be required to adjust the dosage or, in some instances, even discontinue the treatment altogether. 

Your healthcare provider will carefully consider whether the medication needs to be reduced or stopped. If adjustments are required, your doctor may also discuss the possibility of switching to a different GLP-1 medication or exploring alternative therapies. It is important to note that different GLP-1 receptor agonists may have varying effects on individuals, and what works well for one person may not be suitable for another. Therefore, ongoing communication with your healthcare team is key to finding the most appropriate course of action for your specific needs. 

Summary

Listening to your body, particularly to your gut symptoms, plays a crucial role in understanding how you are adapting to GLP-1 therapy. Gastrointestinal symptoms such as nausea, bloating, or mild discomfort are common in the early stages, but they often subside as your body adjusts. However, if symptoms persist or become intolerable, it is essential to take them seriously and communicate them to your doctor. Patience is crucial during this adjustment period, as it can take time for your body to respond to the medication, along with other lifestyle changes, such as diet. 

Equally important is maintaining open and honest communication with your healthcare provider. Do not hesitate to discuss any concerns, whether they relate to side effects, effectiveness, or the pace of the treatment's progress. Your doctor can offer valuable insights, suggest necessary changes, or provide reassurance about the next steps in the process. Staying informed and proactive about your treatment options ensures that you are fully engaged in your health management and empowers you to make decisions that align with your long-term goals. By working collaboratively with your healthcare team and being mindful of your body’s signals, you can optimise the benefits of GLP-1 therapies and enhance your overall well-being.