GLP-1 agonists: Mechanisms, risks and herbal support

GLP-1 agonists are a class of medicines that have revolutionised how we think about obesity and metabolic health. Glucagon-like peptide-1 receptor agonists (GLP-1 agonists), such as semaglutide (Ozempic and Wegovy) and liraglutide, were originally developed for the treatment of type 2 diabetes but are now widely used for weight management.

Tirzepatide (Mounjaro), which acts on both the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, has further expanded the possibilities for pharmacological weight management as it is even more effective than semaglutide (1).

GLP-1-based medicines represent a significant advance in the treatment of obesity and type 2 diabetes, with evidence demonstrating substantial weight loss, improved glycaemic control and reduced cardiovascular risk, particularly when their use is accompanied by physical activity (2). They can also profoundly reduce appetite, slow gastric motility and decrease food intake.

Gastrointestinal symptoms such as abdominal discomfort are common, while reduced food intake can make it more difficult to meet nutritional and protein requirements (3). It is therefore important for herbalists and other practitioners supporting people on GLP-1 agonists to help them manage digestive symptoms, maintain adequate nutritional status, preserve muscle mass and address the wider metabolic picture.

GLP-1 is a naturally occurring hormone released predominantly by intestinal L-cells after food intake. It enhances glucose-dependent insulin secretion, suppresses glucagon secretion when glucose levels are elevated, slows gastric emptying and contributes to the regulation of appetite and food intake. GLP-1 receptor agonists mimic these effects artificially but are modified to resist rapid breakdown, producing a much longer lasting pharmacological effect than endogenous GLP-1 (4).

By slowing down gastric emptying, this results in a reduction in hunger and food intake alongside improvements in blood glucose regulation. This makes GLP-1 agonists particularly useful in type 2 diabetes and obesity. Semaglutide 2.4 mg weekly, the maximum dose of it, produced an average weight loss of 14.9% over 68 weeks in the STEP 1 trial, compared with 2.4% with placebo (5).

Tirzepatide can produce an even greater weight loss than semaglutide. In the 72-week SURMOUNT-5 trial, people taking tirzepatide lost an average of 20.2% of their body weight, compared with 13.7% with semaglutide (1). Tirzepatide has also been shown to produce greater reductions in HbA1c in people with type 2 diabetes (6). This may be partly due to its dual action on the GLP-1 and GIP receptors, compared with semaglutide’s action on GLP-1 alone.

These medicines not only suppress appetite, but evidence shows that weight loss often comes with improvements in several cardiometabolic parameters, including blood pressure, glycaemic control and lipid profiles. In the SELECT trial, semaglutide reduced the incidence of major cardiovascular events by 20% in people with established cardiovascular disease and overweight or obesity who did not have diabetes (7).

Current NICE guidance recommends medicines such as semaglutide and tirzepatide alongside dietary and physical-activity interventions rather than as standalone treatments, as it is well established that they are more effective when combined with physical activity (8,9,10). It is important to introduce these medicines gradually, starting at the lowest recommended dose and increasing slowly according to individual tolerance and clinical response.

For example, both semaglutide and tirzepatide are initiated at low doses and increased at intervals of at least four weeks to reduce gastrointestinal adverse effects. Dose escalation should always be guided by the prescribing clinician, with the aim of finding the lowest dose that provides an effective response and is well tolerated, rather than automatically progressing to the maximum dose, as this is not always necessary (9).

The most common adverse effects are gastrointestinal side effects. Nausea, early satiety, diarrhoea, constipation, abdominal discomfort and vomiting are particularly common, either initially or during dose escalation (11). For many people these symptoms improve with time, but they can be significant enough to interfere with eating and hydration. In STEP 1, gastrointestinal adverse effects were the most frequently reported problems and led to treatment discontinuation in a proportion of participants (5).

GLP-1 agonists also slow gastric emptying. This contributes to satiety but can become problematic in people who already have significant gastrointestinal dysmotility. There are also implications for the absorption of some oral medicines, particularly medicines where relatively small changes in drug exposure can be clinically important (12). 

Gallbladder problems are another potential risk of using GLP-1 agonists. Rapid weight loss itself increases the risk of gallstones, so GLP-1 treatment can add to this risk. A 2025 systematic review and meta-analysis of more than 100,000 participants found that GLP-1 agonists were associated with an increased risk of gallstones and gastro-oesophageal reflux disease (3). Pancreatitis is an uncommon but important adverse event for which patients should be appropriately warned (13). Common symptoms of pancreatitis include intense sharp abdominal pain with vomiting with or without fever.

Other recognised unwanted effects include dehydration and acute kidney injury secondary to significant vomiting or diarrhoea, hypoglycaemia when GLP-1 medicines are combined with insulin or sulfonylureas, and worsening of diabetic retinopathy in people with established retinopathy and a rapid decrease in HbA1c (13, 14). GLP-1 agonists also have warnings concerning thyroid C-cell tumours, so they are contraindicated in people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (15).

Although GLP-1-agonists have been extensively studied, their very long-term safety profile is not yet fully understood, as they have not been in widespread clinical use for several decades. Some potential long-term effects may, therefore, only become evident with longer-term use and post-marketing surveillance. 

Finally, it is important to recognise that while these medicines are effective for weight management, they do not address the underlying factors contributing to obesity, and effects are likely not to be permanent once they are stopped. When semaglutide was discontinued after the STEP 1 trial, participants regained approximately two-thirds of their previous weight loss within a year (16). Similar findings have been reported following tirzepatide withdrawal (1). This reflects the underlying biology of weight regulation rather than a failure of willpower and highlights the importance of longer-term lifestyle changes and support.

One of the less discussed consequences of GLP-1 therapy is simply eating much less. Although this is central to its effectiveness, it can make nutritional adequacy more difficult, particularly in people experiencing persistent nausea, vomiting or early satiety.

There is literature suggesting that micronutrient deficiencies can occur during GLP-1 treatment, although the evidence is still developing. Reduced energy intake could mean that people consume less iron, calcium, vitamin D, B vitamins and protein than they previously did (17).

Lean mass can also decline alongside fat mass during substantial weight loss. This is not unique to GLP-1 agonists as loss of lean tissue happens with many forms of weight reduction. Recent analyses suggest that approximately one-quarter to one-third of weight lost with incretin therapies comes from lean mass, although the exact proportion varies between studies (18). Adequate protein intake and resistance exercise are therefore important for people on GLP-1 agonists.

This means that working alongside a nutritionist can be very beneficial, as it is essential to make sure there is a solid foundation with nutrient-dense meals, sufficient protein, appropriate resistance exercise and correction of clinically-relevant nutritional deficiencies. 

The herbalist approach should be tailored to the specific symptoms and experience of the individual on GLP-1 agonists. The main aim when working with someone who is on GLP-1 agonists should be to help them achieve meaningful improvements in metabolic health while maintaining adequate nutrition, muscle mass, digestive function and quality of life.

Herbs cannot replace the specific action of GLP-1 agonists, however, herbs that gently support metabolism like goat’s rue (Galega officinalis) or gymnema (Gymnema sylvestre) could be helpful. Monitoring blood glucose levels if combining GLP-1 agonists with glucose-lowering herbs is recommended. Some people may need herbs like ginger (Zingiber officinale) if nausea is preventing adequate food intake.

Others may benefit from psyllium (Plantago ovata) if constipation has developed after dietary changes. When abdominal discomfort and dyspepsia are present, it is appropriate to formulate digestive mixtures with carminatives and mucilaginous herbs to sooth the gut lining and address a leaky gut. Some people may also need support with pre-existing metabolic conditions such as subclinical hypothyroidism, for example.

Herbalists also tend to consider the wider clinical picture — oral medications for diabetes, potential blood pressure and lipid-lowering treatment, gallbladder history, gastrointestinal function, nutritional status, alcohol intake, sleep, physical activity and psychological wellbeing.

Herbs for nausea

Ginger (Zingiber officinale) is perhaps the most obvious herb to consider when nausea is prominent. Its antiemetic activity has been investigated in a range of clinical settings, and systematic reviews support a benefit for nausea and vomiting, although the evidence is not specifically derived from people taking GLP-1 agonists (19).

A simple ginger infusion can be sufficient for mild symptoms. More concentrated preparations like ginger tablets can also be considered where appropriate. Other helpful herbs for nausea include peppermint (Mentha × piperita), chamomile (Matricaria chamomilla), fennel (Foeniculum vulgare) and black horehound (Ballota nigra) (20, 21).

Persistent vomiting or the inability to maintain hydration warrants medical assessment.

Herbs for dyspepsia

Peppermint can be useful where there is abdominal discomfort or cramping. Peppermint oil has antispasmodic effects and has demonstrated benefit in functional gastrointestinal disorders (13). Peppermint can also be taken as a hot or cold infusion (20).

Peppermint is not appropriate for everyone, as it can aggravate reflux in some people by relaxing the lower oesophageal sphincter. This is particularly relevant because reflux symptoms can be more common during GLP-1 treatment (3).

Other herbs for abdominal pain or discomfort include antispasmodics with a carminative action like chamomile or fennel, and mucilaginous herbs like marshmallow (Althaea officinalis) and plantain (Plantago major) (21).

Herbs for constipation 

Constipation is another common complaint, particularly when appetite is reduced and food intake changes. Psyllium (Plantago ovata) provides soluble fibre that absorbs water and forms a gel within the gastrointestinal tract. It can support bowel regularity and has also been shown to mildly improve glycaemic and lipid parameters (23). 

It should be introduced gradually with adequate fluid intake. This is particularly important for someone taking a GLP-1 agonist because significant dehydration, severe constipation or suspected gastrointestinal obstruction require medical assessment. Psyllium can also affect the absorption of oral medicines, so taking it separately from medicines is sensible where appropriate.

The role of berberine

Berberine is the main active constituent of plants like barberry (Berberis vulgaris) and Oregon grape (Mahonia aquifolium) and has evidence for mild improvements in glucose and lipid metabolism, with some studies suggesting a small effect on body weight (24).

Its concomitant use with GLP-1 agonists is possible but there needs to be blood glucose monitoring. As the clinical evidence for berberine is not comparable with that for semaglutide or tirzepatide, berberine-containing herbs could be more appropriately considered as supportive option for maintaining weight and cardiometabolic health after GLP-1 agonists are discontinued.

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