GLP-1 Receptor Agonists: A Panacea for All Our Problems? Possibly
Written by Associate Professor Dermot McCaffrey, Consultant Cardiologist and Heart Failure Specialist, Beacon Hospital and St Vincent’s University Hospital
Source: Irish Pharmacy News, June 2026, pages 61–64.
For years, despite encouragement, willpower and the assistance of dietitians and support groups such as Weight Watchers, my patients were overwhelmingly unsuccessful in attaining clinically meaningful weight loss.
Weight loss can improve many aspects of a patient’s quality of life. Benefits may include reduced pressure on weight-bearing joints, such as the hips, knees and ankles; improved diaphragmatic movement during inspiration, which can help reduce the severity of sleep apnoea; and improvements in metabolic markers, including glucose, HbA1c and cholesterol levels.
Previous pharmaceutical agents had significant limitations: dexfenfluramine was associated with valvular side effects; orlistat caused severe gastrointestinal side effects; rimonabant was associated with suicidal ideation; and sibutramine and lorcaserin had cardiovascular side effects. The advent of GLP-1 RA analogues, such as liraglutide in 2014 and semaglutide in 2020, followed by tirzepatide, a dual GLP-1 RA/GIP agonist, has changed the course of many patients’ lives for the better. Triple agonists may soon become available, including retatrutide, which has glucagon receptor agonism, increasing energy expenditure and further reducing hepatic fat accumulation.
So far, no significant adverse outcomes have been reported besides frequent, though not unexpected, GI side effects which can usually be managed by dose titration.
Absolute contraindications include a family history of multiple endocrine neoplasia (MEN) syndrome and type 1 diabetes mellitus. Extreme caution is advised in patients with a history of pancreatitis, unless it was caused by gallstones that have since been treated.
Patients with diabetic retinopathy should only be prescribed the drugs under endocrine guidance as glucose fluctuations may worsen vision related complications.
Mechanism of action: Incretin hormones are gut hormones released in response to eating that lower blood glucose by stimulating insulin release and slowing digestion. There are 2 primary incretin hormones, glucagon-like peptide-1 hormone (GLP-1) and glucose-dependent insulinotropic polypeptide hormone (GIP).
1. Increase insulin secretion from pancreatic beta cells
2. Suppress glucagon, prevents the liver releasing stored glucose
3. Delay gastric emptying, thus slowing the rate at which nutrients are absorbed
4. Induce a feeling of satiety
5. Synthetic GLP-1 receptor agonists are resistant to the usual degradation process by DPP-4 so have a longer half-life so can be given weekly
NB: Sitagliptin and saxagliptin block DPP-4, allowing natural GLP-1 and GIP levels to remain elevated. They are used to manage type 2 diabetes.
Case report 1: 63-year-old male chef living with obesity weighing 100kg, height 168cm, BMI 35.7kg/m² and abdominal circumference 104cm. He had type 2 diabetes and ischaemic heart disease and previous stent as well as hypertension and sleep apnea. He was referred with shortness of breath on effort eg walking up an incline as well as gasping for breath at night and ankle oedema, so GP was concerned about heart failure with PND.
Medications: perindopril 10mg, amlodipine 5mg, metformin 500mg bd, aspirin 75mg and atorvastatin 40mg.
Normal ECG: sinus rhythm 70bpm. Normal echo showing sinus rhythm, normal LV size and systolic function LVEF 60%. Normal valves. Normal relaxation pattern for age.
On examination, BP 140 / 90mmHg. Chest clear. No murmurs. Mild peripheral edema.
Bloods included normal FBC, normal renal function, eGFR 66ml, mildly deranged LFTs consistent with alcohol excess and a fatty liver. He had a normal NTproBNP of 200pg/mL which effectively excluded heart failure in this setting even allowing for the obesity.
Plan: encouraged to go on an exercise and weight loss program, alcohol abstention as well as being prescribed Ozempic 0.25mg weekly x 4 weeks, 0.5mg x 4 weeks and then 1.0mg weekly long term. His amlodipine was also stopped in view of the ankle oedema. He was reassured that the gasping at night was due to his sleep apnoea and not PND.
He was reviewed 12 months later when weight 84kg, height 168cm, BMI 29.8kg/m², abdo circ 94cm and he reported significantly improved effort tolerance. His lipid profile had improved and normal LFTs with NTproBNP now 120pg/mL. His sleep apnoea had improved, and perindopril dose reduced to 5mg as normotensive on ABPM.
The incretin mimetics, namely the GLP-1 RAs and the dual GLP-1 RA/GIP agonist, have additional benefits. These include anti-inflammatory and antioxidant effects, significant reductions in CRP, improved endothelial function and a reduced risk of atherosclerosis. Cardiovascular benefits have also been demonstrated in the SELECT trial in non-diabetic patients with a BMI greater than 27 kg/m² and established cardiovascular disease.
The incretin mimetics have multiple mechanisms of action, although the precise way in which they act on the satiety centre in the brain and reduce reward-driven behaviours is not yet fully understood. Studies are examining their potential role not only in overeating, but also in alcohol and nicotine addiction and other impulse-driven behaviours, such as gambling and shopping. GLP-1 receptors are present in the mesolimbic pathway, and their activation may reduce the dopamine release normally triggered by these behaviours. Patients often report that, when they see a dessert, they no longer feel the same drive or need to have it as they might have previously.
It is important when prescribing these drugs to people who get a lot of joy out of food, let’s call them “foodies”, that they need to think long and hard before going on GLP-1 receptor agonists as it may reduce a certain “joie de vivre”.
However, the benefits of losing weight will hopefully outweigh their loss of food-driven joy.
Case report 2: a 57-year-old man with mild hypertension and sleep apnoea, living with morbid obesity with BMI 38 kg/m². He was prescribed Ozempic but not warned about the Antabuse effect and after watching a rugby game and having a burger and 6 pints of Guinness, ended up in ED with severe dehydration from vomiting and diarrhoea.
An important warning to give patients before starting GLPs is that, because they slow the transit of food, patients may feel bloated, experience more indigestion, burping, farting and possibly constipation. The large studies reported nausea in 22% of patients and diarrhoea in 18%, which is not a small percentage. Nevertheless, the percentage of patients having to stop the drug was approximately 5%.
Advice when uptitrating GLP-1s
If you have GI side effects … ask yourself, could it be alcohol related or dietary indiscretion. Are you taking concomitant drugs e.g. Metformin which someone may be on for NIDDM or for PCOS/PMOS
• Consider skipping next week’s dose and then restart at lower dose i.e. delay uptitrating
• Remember physical activity and diet must be part of the weight loss programme
• Take PPIs such as omeprazole or esomeprazole or Gaviscon prn
• Take laxatives OTC if constipation is the main issue
• Encourage the patient to persist for up to six months, as studies have shown that more than 50% of the benefit is seen by the six-month mark
Remember that Ozempic is not indicated for weight loss but only for management of type 2 diabetes. Ozempic contains semaglutide at doses 0.25, 0.5 and 1.0mg weekly and very recently, they have a 2.0mg Ozempic dose available.
Whereas Wegovy (weight Go Away) has a weight loss indication and has doses containing semaglutide 1.7 and 2.4mg which was used in the weight loss trials.
Patient question: I heard that if I start Ozempic, I must stay on it forever. Is this true? Not necessarily. However, if you stop the injections and have not made the necessary lifestyle and dietary changes, you may regain weight, although you should remain below baseline.
The Step 4 trial published in JAMA, looked at what happens after stopping semaglutide 2.4mg after 20 weeks and showed that patients regain 7% of their initial weight. This study suggests the GLP-1 RA need to be taken long-term unless there is significant behavioural change to maintain the weight loss achieved.
Case report 3: A 60-year-old woman living with obesity, with a BMI of 32 kg/m², was referred for a cardiac review prior to a total knee replacement.; cardiac risks were being a smoker, high cholesterol, hypertension and she was short of breath on effort. Cardiac tests, including a CT coronary angiogram, ECG and echocardiogram, were normal. She was prescribed semaglutide which she self-paid for as she was not a PCRS approved diabetic; HbA1c 44mmol/mol. She was uptitrated over 4 months to Wegovy (semaglutide dose 2.4mg) and she was a “super-responder” losing 15% of her body weight as well as quitting smoking. She was able to defer knee surgery as she had no further pain and reported improved QOL.
Specific recommendations: patients need to stop their injection 2 weeks prior to any major surgery requiring general anesthetic (GA) because the delayed gastric emptying increases the aspiration risk.
Although these medicines are kept in the fridge in pharmacies, patients can be advised that they can keep them in a drawer in their room if they wish. They may want to avoid other people in the household knowing they are on a weight loss promoting agent.
Tirzepatide, trade name Mounjaro, is a more effective weight loss agent than Wegovy as it is a dual agent working on both GLP-1 receptor agonism as well as glucose-dependent insulinotropic polypeptide (GIP). However, it is also more expensive and apparently, the syringe-pen is more cumbersome than the Ozempic/Wegovy delivery pen and needles.
Future possible indications: The incretin mimetics have other positive effects such as improved QOL as measured by the KCCQ scale, improved sleep apnoea indices, reduced systolic and diastolic BP, anti-inflammatory effects with significant reduction in high sensitivity CRP, antioxidant effects, improved endothelial function and improved cardiovascular benefits seen in the Select trial in non-diabetics with BMI > 27kg/m² and established CV disease.
There are studies showing benefits in patients outside of the diabetic and cardiovascular arena; e.g. patients with inflammatory conditions such as rheumatoid arthritis and psoriasis. These drugs are also being used in psychiatry because of the association between depression and obesity as well as being prescribed to counteract the weight gain seen with certain psychiatric meds e.g. olanzapine and certain anti-depressants, e.g. mirtazapine, TCAs like amitriptyline and SSRIs like Lexapro.
In summary, the incretin mimetics have opened a viable weight loss option for many people living with obesity.
Those who are not type 2 diabetics eg HbA1c > 48mmol/mol have to self-pay for the drugs which can be a significant cost to the patient as they are not covered by the drug payment scheme or on a medical card. Nevertheless, some patients report that they can “break-even” from a cost perspective as they are eating out less often, buying fewer treats and especially if alcohol was an element in their calorie excess.
As with many novel therapeutic agents, the incretin mimetics are finding their role in many different areas of medicine. Patients who weigh up the pros and cons of the drugs should be encouraged to at least “give them a try” and then decide after 12 months, whether they wish to continue long term on weekly injections.
The weight loss seen at 12 months on either Wegovy or Mounjaro if titrated to the maximum dose, is generally where patient’s weight will plateau. If patient’s can get to this target, they can then make a personal health/lifestyle decision dependent on whether the benefits they have hopefully noted e.g. better effort tolerance, less discomfort on weight bearing joints, less lower back pain, better quality of sleep with less sleep apnoea and snoring, improved BP indices, improved CV outcomes etc., are worth the cost.
My advice is to try the GLP-1 RA or GLP-1RA/GIP drugs for 1 year and then make an informed decision… but then I’m not the one paying between 250-450/month depending on the product and dose attained.
The pressure to have these drugs at least partly subsidized by the HSE will grow as the health benefits are becoming more obvious across many different patient cohorts. The National Institute for Health and Care Excellence (NICE) in the UK has done extensive health economic evaluations and cost-benefit analysis on Wegovy and concluded that it be prescribed for those with a BMI of 30kg/m² and one weight related comorbidity or simply a BMI > 35kg/m².
The future is looking brighter than a few years ago when all I could advise my patients was exercise, dietary change and a whole lot of disappointment, whereas now my patients who can afford the drugs are achieving clinically meaningful weight loss and significant and measurable life improving benefits.
