Scientific development tends to progress incrementally. But every few decades the relative equilibrium in a particular area will be punctuated by rapid advancement before settling down again. The development of antibiotics, anti-hypertensives and statins are such examples. The fundamental problem is finding a therapeutic target to treat a given condition. This eluded medicine for the disease of obesity until recently. The discovery of the therapeutic targets – the receptors for incretins such as GLP1 and GIP is the revolution in this field. But the magnitude of this particular development is like nothing seen since the development of antibiotics for one simple reason – every organ in the body is affected by the disease of obesity and by treating obesity you treat every organ. It is this connection that underpins the enormous versatility of the anti-obesity medication (AOM). Coupled with this there appears to be reward pathways the brain that are common to satiety and the effects of alcohol, smoking, gambling and even compulsive shopping. More research is needed in these areas to elaborate on the anecdotal reports and small studies that are accumulating.
In this article I briefly describe my own clinical experience with AOM and the discovery that could create a new treatment paradigm for alcohol use disorder. I will describe the potential versatility of the medication and finally provide some advice for pharmacists involved in dispensing the medication. The information provided here is for general purposes only, specific advice should always be sought in respect of specific patients.
Alcohol Use Disorder
My early clinical experience with GLP1 agonists was working on endocrinology in the Mater Hospital where they were used to treat type 2 diabetes. I first started prescribing GLP1 agonists to treat the disease of obesity in 2021 and then set up my own weight management clinic The Medication Weight Loss Clinic in 2022.
Before developing an interest in the disease of obesity I had focused on addiction medicine. This background in addiction medication gave me a context to appreciate the patient feedback on alcohol intake which prompted me to start gathering data in my own clinic on the effects of GLP-1 agonists and alcohol intake.
When I started prescribing the GLP-1 agonists for the disease of obesity the very first problem I ran into with my first patient was that of severe hangovers. I noticed this was something of a pattern with many more patients along with feedback that they felt unwell while drinking. I would advice patients about this in advance of starting the medication. But then I came to realise that this could be presented as a positive health benefit given the deleterious nature of alcohol. As I followed up patients thought 2022 I realised there was a lot more going on with the medication then just exacerbating hangovers. Patients explained that they were too full after their evening meal to drink. When they did drink, they reached satiety very fast and had a very low threshold for nausea. They were drinking at a slower pace which affects the rate of alcohol absorption. The absorption is further reduced by delayed gastric emptying. The slower absorption changes the pharmacokinetics of alcohol and the proportion of acetaldehyde which reduces the pleasurable effects resulting in patients not enjoying the experience as much. Interestingly this is completely the opposite to what happens after gastric bypass surgery where alcohol is absorbed much faster thereby making it more pleasurable and addictive. Clearly there was a negative feedback loop developing with the patients on AOM which appeared to be compounded by a reduction in cravings that may be attributable to the common reward pathways in the pleasure centres of the brain. Overall, patients were simply losing interest in alcohol. I knew from my work with patients suffering from alcohol use disorder that this was remarkable given that there is no pharmacological treatment that I ever found effective for helping them. My research published with Professor Carel Le Roux and Dr Faisal Almohaileb in Diabetes, Obesity and Metabolism found that patients reduced their alcohol intake from an average of 12 to 4 units a week. However, the heavier drinkers reduced from 23 units to 8 units per week, a two thirds reduction. This compared with the 61% reduction reported in clinical trials for nalmefene – a medication approved by the European Medicines Agency for reduction of alcohol consumption. Two points stood out about this – the first was that the medication was giving people control over their drinking which is something every heavy drinker wants rather been told that they have to stop drinking completely. The second point was compliance – a once weekly medication is enormously more effective for a condition like alcohol use disorder because the cravings come in waves which compromises the patient’s commitment to a medication regime. The potential of this medication as an adjunct to treatment for alcohol use disorder is yet to be fully established and will require radomised control trails that will provide a much higher level of evidence. It should not be used for this purpose until there is sufficient evidence to support relevant guidelines.
Future Applications
There are many other conditions that may be treated by AOM as set out below.
Obstructive sleep apnoea – AOM is now commonly used to treat this condition which responds well to weight reduction.
PCOS – a 10% weight reduction is sufficient for clinical improvement in PCOS symptoms including increased fertility.
Cardiovascular disease – ESC 2024 guidelines recommend semaglutide for patients that are overweight with chronic coronary syndrome
Hypertension responds extremely well to weight reduction. Even in the absence of weight reduction there are cardiovascular benefits probably attributable to the reduction in inflammation.
Other conditions may include liver disease, previously known as NASH – now metabolic dysfunction-associated steatohepatitis (MASH), chronic kidney disease – which can be caused by visceral adiposity in a manner similar to MASH and osteoarthritis – due to reduced physical pressure on joints and reduced inflammation.
There are also neurological conditions being examined. It is thought that the benefits accrue from reduced inflammation, reduced deposition of beta amyloid and enhanced brain metabolism. Researchers in Denmark are examining if semaglutide could be used as a treatment of idiopathic intracranial hypertension. Novo Nordisk has a trial testing semaglutide in patients with early Alzheimers disease. Researchers in France are examining the use of lixisenatide for Parkinsons disease.
Advice for pharmacists
The pharmacist has a central role in supporting patients on AOM. Patients with a history of cholelithiasis or pancreatitis need to be cautioned on the signs and symptoms of these conditions because of the risk associated with AOM. Patients should be asked about any history of gastroparesis or ileus as AOM has been associated with these conditions. These conditions would justify a slower titration and close monitoring.
The pharmacist should check any other medication that the patient is on before dispensing the AOM. Patients on insulin or a sulphonylurea are at risk of hypoglycemia. These patients should have a slower titration schedule and consider reducing the sulfonylurea or insulin while monitoring the blood sugars more often. A continuous blood glucose monitor would be particularly helpful during initiation and uptitration.
Female patients of child bearing age should be counselled about contraception because of how AOM reduces gastric emptying and can reduce the efficacy of oral contraception on initiation and uptitration. A second form of contraception should be used in conjunction with oral contraception for 4 weeks after starting and after each dose increase. Patients should stop the mediation at least 2 months before a planned pregnancy.
Constipation should be treated before starting an AOM because of how the medication slows down bowel movements. This can be done with diet adjustments such as increasing citric fruits and avoiding white bread and pasta. If diet is not sufficient then a non-stimulative laxative can be used. The stimulative laxatives should be kept in reserve for acute episodes of constipation.
Nausea is a very common side effect when starting AOM however a minority of patients are very sensitive to AOM and even the starting dose can result in them having severe nausea and difficulty eating anything or even drinking water, risking dehydration and kidney injury. It is extremely important that patients starting AOM understand that while mild nausea is common, vomiting is never normal. Antiemetic medication can be used to counter the nausea if it is severe or there is vomiting but antiemetic medication should only be used if necessary and should not be used on a continual basis. If there is severe nausea or vomiting the dose is too high and needs to be reduced. If this happens the patient should be referred back to their prescribing doctor to have the dose reduced.
Lifestyle advice should include regular exercise, a high fibre diet, good hydration and an OTC multivitamin to prevent micronutrient malnutrition.
It’s very important that the patient knows how to use the dispensing pen. Many pharmacists are comfortable showing patients how to count the clicks to dispense a dose other than the assigned dose of the pen. This is an off-license use of the device but is now reasonably common practice and considered safe. It is necessary to know how many clicks make up the assigned dose for that particular pen and then use a proportionate number of clicks for the desired dose. Patients will need extra needles to do this.
Many patients living with the disease of obesity have an unhealthy relationship with the scales. Sensitivity should be paramount when questioning a patient about their weight. A visual inspection is often sufficient to establish that a patient has an elevated BMI. In the event that a visual inspection raises suspicion of a patient being underweight then further questioning is justified. If a patient’s weight is to be checked it should be done with their expressed consent and in a part of the premises that is private.
Repeat Prescriptions
When a patient is returning for a repeat prescription there are important questions to ask. Firstly, that the bowels are moving regularly and that any constipation is mild. As previously mentioned, diet can be used to mitigate constipation, exercise after eating aides gut mobility and adequate hydration helps. A regular bulking agent can used added if necessary.
Diarrhoea is usually transient on initiation or dose increase and is rarely an ongoing problem. The risk of treating it is rebound constipation. An oral electrolyte replacement can be used but if loperamide is used the patient will have to be referred back to the prescribing doctor for dose adjustment because the risk of constipation which is a more serious problem.
As previously mentioned nausea is common but vomiting is not acceptable. Nausea can be mitigated by eating more slowly, eating regular smaller meals, avoiding spicy, fried or greasy foods and drinking cold water. Importantly the patient should not increase the dose of their medication as scheduled if there is any significant nausea, diarrhoea or constipation.
Acid reflux can improve when on AOM due to smaller meals and not eating at night but it can get worse due to delayed gastric emptying. It can be mitigated by avoiding alcohol, smoking, spicy foods, eating late at night and identifying triggers by keeping a food diary. If conservative measures are insufficient then any of the OTC medications can be used such as a PPI.
Sulphur burps are a related side effect which are more difficult to treat but they rarely persist. Treatment options include trying a pro-biotic and peppermint tea or extract. Avoiding sulphur rich foods and ensuring good hydration can also help.
Finally, it’s important to be aware that many patients have had very bad experiences previously with healthcare professionals and may be sensitized to any perceived judgement or stigma. It’s vitally important to display a non-judgemental supportive approach.
Conflict of Interest
Dr Maurice O’Farrell provides obesity clinical care in The Medication Weight Loss Clinic and is the owner of this clinic. He has served on advisory boards for Novo Nordisk and Johnson & Johnson, both positions unremunerated.
Written by Dr Maurice O’Farrell, The Medication Weight Loss Clinic
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