Overview

Glucagon-like peptide 1 receptor agonists (GLP-1) are medicines used to treat type 2 diabetic patients and as a weight loss management in obese patients. The drugs are the modified versions of the GLP-1 hormone that naturally occurs in the body. These drugs mimic the effects of GLP-1 when released as a response to ingesting food. The hormone induces insulin release and is involved in regulating blood sugar levels. It also prevents the production of glucagon, a hormone that raises blood sugar. These two mechanisms help in treating patients with type 2 diabetes. For patients using GLP-1 receptor agonists for weight loss management, the drug also has an added benefit in reducing the rate at which the stomach empties, which results in a decrease in appetite and feeling fuller for longer, promoting weight loss.¹

Five GLP-1 receptor agonists are currently available in the UK market: exenatide (Bydureon BCise®), liraglutide (Saxenda®, Victoza®), dulaglutide (Trulicity®), semaglutide (Wegovy®, Ozempic®), and tirzepatide (Mounjaro®). These drugs are injected subcutaneously (into the fatty tissue layer beneath the skin) into the thigh, abdomen, or upper arm.²

Currently, the only GLP-1 receptor agonists licensed for weight management are Saxenda®, Wegovy® and Mounjaro®.³

Side effects

Like with many drugs, GLP-1 receptor agonists also cause adverse effects. The most common side effects with GLP-1 receptor agonists include: 

• Nausea and vomiting
• Diarrhoea
• Pain in the stomach
• Constipation
• Indigestion
• Lack of appetite
• Low blood sugars
• Headaches
• Local skin reactions after injection

However, symptoms usually taper off as therapy continues, especially for symptoms involving the digestive system.^4,5 However, for some individuals, these symptoms can be difficult to tolerate, and they may require tapering off the GLP-1 receptor agonist and switching over to an alternative or a different drug altogether.

Furthermore, as GLP-1 receptor agonists reduce how fast the stomach empties its contents, this can be an issue for patients who undergo surgery and are under general anaesthesia. This means that despite fasting before the surgery, there is a potential risk of pulmonary aspiration (stomach contents such as food or liquid get inhaled and enter the lungs and windpipe). This can lead to infection and cause further complications in the surgery.⁶

Reasons for discontinuation

The reasons for discontinuing GLP-1 receptor agonists can be due to various factors. It can be due to inadequate blood sugar control from the drug, being intolerable to the adverse effects such as nausea and vomiting, the cost of the medication, the preference for oral medication and not injections, the patient unable to reach their weight goal, weight gain and injections being painful to inject. However, it is not recommended to entirely stop treatment without weaning the drug gradually.⁷

Complications of sudden discontinuation

Abrupt withdrawal of GLP-1 receptor agonists can cause adverse effects. These include fast weight gain and the potential for idiopathic intracranial hypertension (an increase in pressure around the brain, causing painful headaches where the cause is not established).⁸ In some individuals, sudden withdrawal can cause their body weight to revert to the previous weight, or close to it, within a few months. Patients may also gain more weight than their original weight.⁹

Weaning off

It is recommended that GLP-1 receptor agonists be weaned off gradually to ensure that the amount of weight lost is maintained for patients using the drug for weight loss management. In a study that looked at semaglutide in particular, in which patients were gradually tapering doses according to an agreement with their healthcare professional, they achieved a stable body weight in the first 26 weeks.¹⁰

In type 2 diabetics, the use of GLP-1 receptor agonists is monitored. According to the NHS Bedfordshire, Luton and Milton Keynes Area Prescribing Committee guidelines, patients are reviewed 6 and 12 months post-therapy. At the 6-month review, GLP-1 receptor agonists only continue if a response is observed. This means that the patient’s average blood sugar within two to three months (HbA1C) has to decrease to at least 11 mmol/mol (1.0%). In addition, patients need at least a 3% reduction in original body weight for treatment to continue. Then, at the 12-month review, the GLP-1 receptor agonist may be stopped if there is no continual response after 6 months of treatment. Therefore, to ensure no fluctuations in blood sugar levels, GLP-1 receptor agonists should be tapered off steadily.¹¹

There is no universal regimen for weaning off GLP-1 receptor agonists. Weaning off a drug can differ from person to person. Some individuals can wean off faster than others, especially if they are on a lower dose and have not been on the GLP-1 receptor agonist for long, in comparison to patients on the maximum dose and have been on the drug long-term.

Therefore, it is recommended to speak to a healthcare professional so that they can generate a treatment plan that suits your weight goals.

A potential reduction regimen can be as follows: similarly, when first initiating the drug, it can be tapered off in the same pattern.

Mounjaro®: Patients can try to wean off every 4 weeks in 2.5mg dose increments. Patients should not try to taper off faster than 4 weeks. Therefore, from the maximum dose of 15mg, the patient stays on this dose for 4 weeks, then gets reduced to 12.5mg, then 10mg, then 7.5mg, then 5mg, then 2.5mg for 4 weeks, and then stops treatment.

Wegovy®: Patients can try to wean off every 4 weeks in 0.7mg dose increments. Patients should not try to taper off faster than 4 weeks. Therefore, from the maximum dose of 2.4mg, the patient stays on this dose for 4 weeks, then gets reduced to 1.7mg, then 1mg, then 0.5mg, then finally 0.25mg for 4 weeks, and then stops treatment.

Saxenda®: Patients can try to wean off every 1-2 weeks if tolerated in 0.6mg dose increments. Patients should not try to taper off faster than 1 week. Therefore, from the maximum dose of 3mg, the patient stays on this dose for 1-2 weeks, then gets reduced to 2.4mg, then 1.8mg, then 1.2mg, then 0.6mg for 1-2 weeks, and then stops treatment.

Diet and exercise

Although GLP-1 receptor agonists are shown to be effective in weight loss management, patients should continue to have lifestyle modifications in place. This can be through changes in their diet and increasing their physical activity during therapy and after weaning off the drug to ensure weight loss is maintained. In addition to reducing alcohol and sugar intake and stopping smoking. For example, the Mediterranean diet has been shown to encourage weight loss and has additional benefits in reducing the risk of heart complications developing in the future. The diet consists of increased intake of whole grains, fruit and vegetables, fish, nuts, legumes and pulses, unsaturated fats (considered healthier than saturated fats), and less red meat consumption. This is especially important because when you are weaning off GLP-1 receptor agonists, GLP-1 in the body is reduced, making you feel more hungry. Therefore, the Mediterranean diet is a healthy diet that ensures that you feel fuller for longer and allows weight loss to be maintained.

Exercise is also key to ensuring weight loss after tapering off treatment. Some exercise suggestions can be as follows: 30 minutes of walking, 20 minutes of brisk walking, 10 minutes of jogging, or 5 minutes of strenuous exercise such as basketball, swimming, or jumping rope per day. For patients less than 50 years old, it is recommended that they perform two exercises per day.¹³

Summary

GLP-1 receptor agonists are used in treating patients with type 2 diabetes and in obesity management. The drugs come in injectable device pens that help lower blood sugars and help you feel fuller for longer. However, it can come with unpleasant adverse effects such as nausea and vomiting, which some patients find intolerable. Therefore, patients should consult with their healthcare provider if they need to switch to a different GLP-1 receptor agonist or an alternative drug. When patients have met their weight goals during their treatment, it is advised again to speak to their healthcare provider about the future steps in their treatment, and to wean off if necessary, according to their assigned treatment plan.