Background on obesity disease and management A multi disciplinary approach   Obesity is understood to be a complex, progressive and relapsing disease Obesity and its related complications mainly Type 2 diabetes mellitus, cardiovascular disease and cancer are the number one cause of mortality in our Western society   The therapeutic aim is to achieve sustained long term clinically relevant weight loss (primary end point) and resolution of obesity related medical co-morbidities (secondary end points) *Treatment of obesity needs to be targeting 3 broad categories, which include behavioural intervention, metabolic bariatric surgery and pharmacotherapy   Obesity is also preventable with behavioural, medical interventions and surgery, however the uptake of metabolic bariatric surgery across the world remains low, with about 1% of patient eligible elect to have surgery *Hence glucagon like peptide 1 receptor agonist (GLP-1 RA) injections is seen as a viable option to address this inequality *But clinicians need to decide if or when to introduce the GLP-1 RA treatment into the management algorithm for the treatment of obesity and T2DM, this proves to be more difficult

Background on metabolic bariatric surgery vs GLP-1 RA injections Expert opinion IFSO 2024 statement 1. Metabolic and bariatric surgery Bariatric metabolic surgery has been performed for many decades *with a robust body of evidence supporting long term efficacy, durability and cost effectiveness *is still the gold standard for treatment of morbid obesity and obesity related medical co-morbidities in terms of long term optimal weight loss, improvement in health related quality of life and reduction in obesity related or all cause mortality *after gastric bypass surgery the post prandial release of GLP-1 is intermittent   Pharmacotherapy is emerging and is in its early phase at the moment *not many have long term studies beyond 5 years *after pharmacotherapy there is continuous stimulation on the GLP-1 receptor, long term side effects are still unknown 2. Subcutaneous injections for weight loss   Modern pharmacotherapy has changed the landscape of the treatment of obesity and its complications in the last year   However there is a wide knowledge gap regarding the important points in contemporary obesity treatments *Future studies need to include weight loss and remission/improvement of obesity complications outcome regarding the added benefits of metabolic bariatric surgery plus obesity management medications   Obesity management medications should not be viewed as a competitor to or replacement for metabolic and bariatric surgery but as a useful adjunct *After gastric bypass surgery the post prandial endogenous release of GLP-1 is intermittent and exogenous medications has been developed and may be used to the patients’ advantage *The mechanisms may be similar or slightly different   GLP-1 receptor agonist such as Liraglutide (Saxendra), Semaglutide (Ozempic, Wegovy) and the dual GIP + GLP 1 RA Tirzapatide (Mounjaro) are currently (2025) available in Australia *These agents have demonstrated weight loss ranging from 5 to 15% along with significant reductions in cardio metabolic risks *Trials for liraglutide (SCALE), for semaglutide (STEP, SUSTAIN, PIONEER) and tirzapatide (SURMOUNT, SURPASS) are ongoing   Currently it is recommended that for patients using the GLP-1 RA should complete at least 12 weeks of continuous therapy to achieve clinically meaningful weight loss with corresponding health benefits *However there may be issues with patient adherence to the injections due to factors such as cost, supply issues and side effects *Discontinuation of pharmacotherapy was associated with weight regain of 2/3 of the weight loss and loss of the benefits on cardiometabolic risk factors within 1 year *Currently the major issue is the long term cost effectiveness and supply chain issues   Currently there is a paradigm shift in terms of understanding obesity (similar to Type 2 diabetes mellitus) and its metabolic impacts on health. That is   Obesity should be regarded as chronic long term multifactorial and multi stage disease *Obesity management medications should be considered a requirement for the longer term (not just a few months or a year) *Obesity surgery should be regarded as integral to the subgroup of patients who meets the criteria for metabolic and bariatric surgery In the future there may/will be more evidence for the combined treatment for obesity with both metabolic bariatric surgery and GLP-1 RA medications in a synergistic or adjuvant role to integrate both into the management for obesity

Mechanism of action and side effects of GLP-1 RA injections   GLP-1 RA injections play an important part in the management of obesity and its related metabolic co-morbidities (especially T2DM) because of the incretin effect   In simple terms the mechanism of action for GLP-1 RA injections is the incretin response *Stimulates insulin release *Supress glucagon secretion *Reduce gastric emptying and increase satiety   Adverse effects of GLP-1 RA injections *The most common are GIT related side effects such as nausea, vomiting and diarrhoea *These side effects are dose dependent, often experienced at the time of initiation of therapy or dose escalation *There may be delayed onset of acute pancreatitis with increased in amylase level *With rapid weight loss, attenuation of cholecystokinin stimulated gall bladder emptying, there is an increase the risk of gallstones, acute cholecystitis and biliary obstruction *With delayed gastric emptying there is a risk for pulmonary aspiration and post op nausea/vomiting especially those within 8-12 weeks of surgery

The mechanisms of GLP-1 RA injections after metabolic bariatric surgery are complex *In obese individuals the fasting and post prandial GLP-1 levels are lower than normal weight individuals *After bariatric surgery, most patients have a significant elevation in post prandial GLP-1 levels (but not so much for the fasting GLP-1 levels) *Patients with SICR and WGR don’t have as much rise in the fasting or post prandial GLP-1 levels (compared to patients with good weight loss results after surgery), leading to hunger and increase in appetite *Administration of GLP-1 injection augments the endogenous fasting GLP-1 level, assist in reducing appetite and enhancement of satiety and also sustain elevation of post prandial GLP-1 levels (similar to what is seen after bariatric surgery)   *GLP-1 injections also reduce hepatic glucose production, improve insulin sensitivity and enhance B cell function contributing to weight loss, diabetes control and other metabolic benefits   Experts have studied and described that endogenous GLP-1 also participates in adipocyte development, plasma clearance of tri-acyl derived fatty acids, stimulation of adipose brown tissue, promoting neurogenesis, reduce inflammation and improve cognitive function (learning, memory)   Research and studies into the cell mitochrondria function is ongoing   It is difficult to perceive that exogenous GLP-1 either in the form of subcutaneous injection or tablet will replace all these vital functions *So far the clinical effects are promising

GLP-1 RA use in the pre or post op setting Previously trials have reported the benefits of GLP-1 in promoting weight loss for patients with obesity and T2DM who did not have bariatric surgery. The caveats are *GLP-1 injections are more suitable for patients who does not meet the criteria for bariatric surgery or patients who are not surgical candidates because of various other reasons *Bariatric and metabolic surgery is still the most effective treatment modality, have superior weight loss outcome, more significant rates of improvements for obesity related metabolic parameters (better efficacy), has better long term outcomes (better durability) and is more cost effective than weight loss injections   But nowadays especially in the last few years (beginning in 2024 to 2025) we have also seen a huge uptake and increase in prescriptions for GLP-1 RA injections not just for non surgical candidates but also increasing being used in the pre-op setting and for post-op patients as well as an adjunct *Nowadays considerations are given to introducing the GLP-1 RA injections as step approach rather than surgery first approach to the treatment of obesity *GLP-1 RA is now being used more often as adjunct after metabolic bariatric surgery   The GLP-1 RA injections was initially developed for glycaemic control for Type 2 diabetes patients these agents demonstrated potent weight reducing loss effects through enhanced satiety, delay gastric emptying and decrease caloric intake *It was prescribed instead of metabolic bariatric surgery   GLP-1 RA is now considered to be an important complement rather than a replacement for metabolic bariatric surgery GLP-1 RA has become an important tool in the pre-op as well as post-op setting to optimize patient outcomes *Pre-operatively this bridging therapy aims to promote weight loss, improve metabolic parameters, reduce liver size, potentially reduce the technical difficulties of the surgical procedure *Post operatively the adjunct therapy may be of assistance in the suboptimal weight loss or recurrent weight gain patient groups   However recent studies on the pre-op use of GLP-1 RA have not proven to be as effective as we hoped for   In contrast there are literature to support the use of GLP-1 RA as adjuvant therapy after metabolic bariatric surgery. This will be described in more detail below.

Pre-operative GLP-1 RA injections A systematic review   One systematic review of pre-op use of GLP-1 RA injections showed: *The total weight loss (TWL) in the pre-op GLP-1 RA users was the same or less than patients who did not received GLP-1 RA injections ***Patients who did not receive GLP-1 RA injections did achieve more weight loss after surgery but this was not statistically significant *There were no significant differences in rates of peri-operative or post operative complications between the two groups *But there were higher rates of post op nausea and vomiting in the GLP-1 RA user group   The benefits of GLP-1 RA *Improve glycaemic control for T2DM before surgery *An important predictor for the success for metabolic bariatric surgery   The adverse effects of GLP-1 RA: *These medications will cross the blood brain barrier affecting areas of the brain which normally affects the regulation of nausea *The gastroparesis or delayed gastric emptying potentially increase the risk for regurgitation and aspiration *There is a higher risk of pancreatitis, potentially increasing the adhesions of the posterior gastric wall *There may be reduction in gall bladder motility or emptying

Post-operative GLP-1 RA injections   Systematic reviews have reported on the efficacy and safety of GLP-1 RA injections in the treatment for patients with obesity and or T2DM after bariatric surgery *The GLP-1 RA injections may be used on some patients who desire to achieve more weight loss before resorting to revision surgery straight away *In patients with inadequate weight loss GLP-1 RA injections is a useful adjunct *Recent study showed that 2/3 of the weight regain may be treated with GLP-1 RA injections   Because obesity is now seen as a relapsing condition *Weight regain and return of diabetes or cardiovascular disease occur with time *This is normal after any types of bariatric procedures   Nowadays many GP as well as endocrinologist are actively prescribing these medications for patients after bariatric surgery as an adjunct to the surgical treatment for obesity, T2DM and other metabolic medical co-morbidities

Background information on the use of GLP-1 RA injections: For suboptimal initial clinical response (SICR) and weight gain recurrence (WGR)   Statistics in 2022 reported that over 890 million of adults around the world are affected by obesity *Bariatric surgery has proven to be an effective treatment for obesity resulting in 20-35% TBW loss and significantly reducing the incidence of obesity related complications and all cause mortality *But 15-40% patients experience inadequate weight loss or weight regain after initial success of surgery   With weight regain there may be a return of cardio-vascular risk factors (recurrence of dysregulated glucose and lipid metabolism), psychological impact (anxiety, depression, binge eating)   Inadequate weight loss is termed suboptimal initial clinical response (SICR) Weight regain is also described as weight gain recurrence (WGR)   Unfortunately the treatment options currently for SICR and WGR are limited Options include: *Continue with optimization of lifestyle changes, dietitian and exercise physiologist assessment *GLP-1 RA or combination GIP-1 with GLP-1 RA injections *Revision or converted bariatric procedures   Patients need to be warned about SICR and WGR and the reasons for less than satisfactory outcomes after initial surgery, which may include: *Certain non technical factors that can’t be changed, such as age, genetics, metabolism, hormonal factors, thyroid function, medications with weight gain side effects (insulin, steroids, anti depressants, etc)   *Many patients have already attempted intensive dietary and lifestyle interventions before bariatric surgery without optimal/satisfactory sustained clinical response, hence to continue down this route is likely to be futile *Some patients have already tried the GLP-1 RA injections before bariatric surgery with limited success, intolerances or affordability issues (cost prohibitive in the medium to long term) hence to recommend GLP-1 RA injections again may be ineffective *Revision endoscopic bariatric procedures are rarely performed and the results are unpredictable *Revision bariatric surgery is often seen as a last resort and it does not guarantee success, may have follow up issues, side effects, more risk and complications after surgery   Revision surgery have a reported weight loss ranging from 7 to 24% TBW and carries a high risk for complications, especially leak, infection, fistula, diarrhoea, hypoglycaemia and nutritional deficiencies   Hence it is important to understand and appreciate the role for GLP-1 RA or dual therapy GIP-1 and GLP-1 RA injections in our patient group described above before resorting to revision surgery straight away *In comparison GLP-1 RA injections has similar weight loss outcome (10-15% TBWL) with no operative/surgical complications and less GIT side effects *GLP-1 RA injections have a more tailored personalized treatment with dose adjustments possible *There will be a lot more studies on GLP-1 RA over the next few years, the long term results and adverse events will be better reported and more information will be available

Summary of clinical studies for GLP-1 before or after bariatric surgery   Randomised STEP trails compared outcomes of weekly subcutaneous injections of Semaglutide vs placebo/lifestyle modification for patients with obesity with or without diabetes *Showed significant weight loss and is sustained up to 2 years   Other trials demonstrated TBW of 10-12.5%, reduction in BMI and waist circumference   High dose semaglutide is more effective than low dose semaglutide, oral semaglutide and other GLP-1 for weight loss   Studies indicate that GLP-1 RA after bariatric metabolic surgery results in additional weight loss   The GLP-1 RA is effective after any types of bariatric surgery (band, sleeve, bypass) and is equally efficacious in both primary and revisional procedures   Recent studies (from Sydney) *Reported adequate weight loss can be achieved when using only 1mg/week which has significant cost savings *The patient may choose a cost effective dose with a focus on prolonged therapy rather than escalated therapy *The side effects include nausea, vomiting, GIT upsets and delayed gastric emptying (less problematic after RYGBP)

The clinical use of post op GLP-1 RA injections   GLP-1 RA injections (liraglutide, semaglutide, tirzapetide) are associated with significant weight loss for some patients with SICR after weight loss surgery *There are also improvements in metabolic parameters (reduction in triglyceride, total cholesterol, LDL, HbA1C and ALT levels) *Some have shown improve dyslipidaemia, reduce systolic blood pressure, delayed progression of atherosclerosis, regulate inflammation and reduce cardiovascular health   However determining the optimal timing, duration and choice of GLP-1 RA therapy in post bariatric patients is critical for maximizing therapeutic benefits *There are no current guidelines to determine when or how to introduce these injections   Most studies previously have reported interval between bariatric surgery and initiation of therapy is beyond 5 years *However recent evidence indicate that earlier administration is beneficial for SICR or WGR *Also for patients with a higher baseline weight weight, adjunct GLP-1 to enhance weight loss outcome before SICR or WGR may be appropriate ?   Regarding the choice of GLP-1 RA injections it was reported that Semaglutide and Tirzepatide has better efficacy than Liraglutide   Regarding the duration of treatment longer term use beyond 12 months may lead to better weight loss outcomes

Pharmacotherapy for recurrent weight gain after bariatric surgery: IFSO statement 2024   Pharmacotherapy should be included in the multi disciplinary treatment plan for recurrent weight regain (RWG) *However the timing to initiate pharmacotherapy or the duration of use is not known   Obesity management medications include oral tablets (phentermine, topiramate) individually or in combination can reduce RWG after RYGBP *There is a report of 30.3% of patients losing >10% TWL *Topiramate is the only medication that demonstrated statistically significant response for weight loss *The weight loss response rate is less for patients who had the sleeve gastrectomy compared to RYGBP     Obesity management medications with GLP-1 RA injections showed good results in the short term *Liraglutide 3mg/day for 12 months there is a loss of 5% TWL (for 75% of patients) and 10% TWL (for 25% of patients)   The GRAVITAS is a RCT trial using liraglutide 1.8mg/day vs placebo in patients with persistent or recurrent T2DM 1 year after sleeve or RYGBP *Patient on liraglutide lost more weight and has better glycaemic control than placebo   Another small RCT add liraglutide early on after sleeve gastrectomy compared to placebo *Liraglutide added early after LSG significantly augments weight loss   The Bari-Optimise RCT recently published the efficacy and safety of liraglutide 3mg vs placebo for patients with <20% TWL after sleeve or RYGBP *Liraglutide 3mg for 24 weeks led to significant reduction in %TWL compared to placebo with improve cardio-vascular risk factors and quality of life   There are very few results with Semaglutide in trials for SoCR and RWG after bariatric surgery for now *One trial reported semaglutide 0.5mg/week to have a mean of 10.3% TWL (85% of patients achieve >5% TWL after 6 months)   Semaglutide phase 3 trial STEP-1 reported 2% reduction in body weight within the first 4 weeks of treatment (early responders) and these patients continue to lose weight throughout the 6 month follow up period     One study of GLP-1 RA therapy for RWG 12 months after bariatric surgery reported a median 8.8 %TWL after 6 months *>3/4 patients lost over 5% baseline weight, >1/3 lost over 10% baseline weight *The median patient lost 67.4% of the weight regained (but not 100%) after bariatric surgery   There is no data on the use of obesity management medication before patient reached their plateau

Semaglutide (Ozempic or Wegovy) injections For our Australian population   Some patients after surgery may benefit from GLP-1 RA injections for 2 indications: *Inadequate weight loss (suboptimal initial clinical response SICR)* *Weight regain with medical co-morbidities (weight gain recurrence WGR)   However these injections are costly and supply may be limited   The oral form of Semagultide is not yet available in Australia but will (or hopefully will) be in the future       Prescription for Semaglutide is dependent on response to treatment, tolerability, availability and affordability   The median dose of subcutaneous injection of Semaglutide is 1mg/week *78% of patients can tolerate up to 1mg/week *The median total weight loss is about 7.5% *The duration is usually over 6 months but most patients discontinue this after 12 months   In 2025 The Australia Pharmaceutical Benefits Scheme (PBS) has approved the use of Semaglutide 0.5 to 1mg for management of T2DM   The average monthly cost of 1mg Semaglutide (Ozempic) is about *$42 (PBS for patients with diabetes) *$150 (private script for obesity without diabetes)   Higher doses of Semaglutide (Wegovy) is 1.5 times more expensive on a private script   The Therapeutic Goods Administration (TGA) is studying the use of high dose semaglutide (Wegovy) 2.4mg for management of obesity in Australia

Oral GLP-RA agonist medication (from Novo Nordisk)   Late in 2025, Rybelsus an oral tablet version of GLP-1 RA has been introduced in Europe following positive results from the SOUL trial *Currently Rybelsus is the only oral GLP-1 RA tablet for the treatment of T2DM *Currently (in 2025) Rybelsus is not prescribed for weight loss in Australia   SOUL was an international multicentre, randomised double control phase 3 trial assessing oral Semaglutide vs a placebo, a trial started in 2019   The SOUL trial demonstrated: *Superior reduction in major adverse cardiovascular event (MACE) by 14% in patients with T2DM, cardiovascular disease and/or chronic renal disease *Significantly reduced hospitalizations related to serious events *The cardiovascular benefits were consistent regardless of body weight or BMI   The same Novo Nordisk company who produces Rybelsus have recently submitted an application to produce oral Semaglutide (Wegovy in tablet form) as well to treat adults with obesity and cardiovascular disease

Oral GLP-RA agonist medication (from Eli Lilly) Orforglipron (6mg, 12mg, 36mg) vs placebo has been evaluated in 2 trials *Currently (in 2025) Orforglipron is not available in Australia     Attain-1 (study for obese patients without T2DM) *Mean weight loss 7.5% (6mg), 8.4% (12mg) and 11.2% (36mg) vs 2.1% (placebo) *>10% weight reduction was achieved in 54.6% of patients (on 36mg) vs 12.9% (with placebo) *There were improvements in waist circumference, systolic blood pressure, triglycerides and non HDL cholesterol *Discontinuation rate due to side effects is 5.3 – 10.3% (orforglipron) vs 2.7% (placebo)   Attain-2 (study for obese patients with T2DM) *Mean weight loss 5.5% (6mg), 7.8% (12mg) and 10.5% (36mg) vs 2.2% (placebo) *>10% weight reduction 23.9% (6mg), 35.5% (12mg) and 50.1% (36mg) vs 7% (placebo) *>15% weight reduction 7.3% (6mg), 17.7% (12mg) and 28.4% (36mg) vs 1.9% (placebo) *HbA1C reduction from baseline of 8.3: 1.3% (6mg), 1.6% (12mg) and 1.8% (36mg) vs 0.1% (placebo) *HbA1C <6.5% achieved in 75% (on 36mg) vs 10.6% (placebo) *There were improvements in non HDL cholesterol, triglycerides, systolic blood pressure and reduction in CRP *Discontinuation rate due to side effects is 6.1% (6mg), 10.6% (12mg) and 10.6% (36mg) vs 4.6% (placebo)   Achieve-1 (T2DM without medications, orforglipron vs placebo) *Mean weight reduction 4.5% (6mg), 5.8% (12mg) and 7.6% (36mg) vs 1.4% (placebo) *Reduction in HbA1C 1.24% (3mg), 1.47% (12mg), 1.48% (36mg) vs 0.41% (placebo) *Discontinuation rate 4.4 – 7.8% vs 1.4% (placebo)   Achieve-3 (T2DM inadequately controlled on Metformin, orforglipron (12mg, 36mg) vs oral Semaglutide (7mg, 14mg)) *Mean weight reduction 6.7% (12mg) and 9.2% (36mg) vs 3.7& (7mg) and 5.3% (14mg) *Reduction in HbA1C from baseline 8.3: 1.9% (12mg) and 2.2% (36mg) vs 1.1% (7mg) and 1.4% (14mg) *Discontinuation rate 8.7% (12mg) and 9.7% (36mg) vs 4-5% (oral semaglutide)

Future direction and trends

It is difficult to predict the trend for GLP-1 RA injection use in the future especially when the oral tablets are coming in the future.

Currently the injections may have a limited durability of use due to cost and side effects as well as a less superior weight loss outcome and health improvements.

MBS is better than GLP-1 RA injections in the long term   Nature Medicine 2025. Gasoyan H, Alavi M, Zajichek A, et al. Macrovascular and microvascular outcomes of metabolic surgery versus GLP-1 receptor agonist in patients with diabetes and obesity.   This is a large Cleveland clinic study, which found that people with obesity and T2DM who undergo metabolic and bariatric surgery live longer and has fewer adverse health issues compared to those treated with GLP-1 RA agonist medicine alone. *Patients tend to stop using GLP-1 RA injections over time and the benefits can’t be sustained   Patient who had surgery lost more weight, achieved better glycaemic control and relied less on diabetes and cardiac medications over 10 years. *On average people who had MBS lost 21.6% TBW over 10 years compared to 6.8% TBW in people who had GLP-1 RA injections *HbA1C improved more with surgery (0.86%) than GLP-1 RA (0.23%) *Patients who had surgery required fewer prescriptions for diabetes, high blood pressure and cholesterol   The M6 (Macrovascular and microvascular morbidity and mortality after metabolic surgery vs GLP-1 RA) with 10 years follow up reported that patients who had MBS had: *32% lower risk of death *35% lower risk of major heart problems (such as heart attack, heart failure, or stroke) *47% lower risk of serious kidney disease *54% lower risk of diabetes-related eye damage (retinopathy)

MBS achieves greater weight loss and has lower ongoing cost than GLP-1 RA injections   JAMA 2025. Barrett T, Hafermann J, Richards S, et al. Obesity treatment with bariatric surgery vs GLP-1 receptor agonist   This is an American study using the Highmark Health insurance claims database, found that surgery was significantly associated with greater weight loss (3 times more), less obesity related complications (hyperlipidaemia, obstructive sleep apnoea) and less emergency department visits while saving $ 11 689 in ongoing cost over 2 years *Surgery has 18% lower cost

High rates of discontinuation of GLP-1 RA injections   The recent Annual Meeting of the European Association for the Study of Diabetes Vienna reported that half of the adults patients without diabetes in Denmark discontinue Semaglutide (Ozempic) within a year   This is concerning because these medications aren’t meant to be a quick fix, for it to work effectively they need to be taken long term. All the beneficial effects on appetite control are lost if the medication is stopped.   The reasons are cost related and side effects of the medication *GLP-1 RA injections are expensive (about 2000 Euros/year for Semaglutide in 2025) *Patients with GIT side effects such as nausea, vomiting, diarrhoea are 9% more likely to discontinue Semaglutide within 1 year *People with psychiatric medications are 12% more likely to discontinue within the first year *Patients with cardiovascular disease and other chronic medical conditions were 10% more likely to discontinue treatment early *Men were 12% more likely to stop the treatment compared to women Obesity 2025. Gasoyan H, et al. Reasons for discontinuation of obesity pharmacotherapy with Semaglutide or Tirzapetide in clinical practice. The Cleveland Clinic in USA reported that the common reasons for treatment discontinuation within the first year of treatment are: *High cost of the GLP-1 RA injections (47.6% of the patients) *Intolerable side effects (14.6%) with nausea, abdominal pain, vomiting, diarrhoea, depression *Medication shortages (11.8%) *Unsatisfactory weight loss (10.8%) *No specific reasons (11.1%)