Introduction

Changing trends to prescribing GLP-1 injections after surgery

Previously trials reported benefits of GLP-1 in promoting weight loss for patients with obesity and T2DM who did not have bariatric surgery. The caveats are

• Bariatric and metabolic surgery have better total body weight (TBW) loss outcome, improvements in metabolic parameters, with better long term outcomes and is more cost effective than weight loss injections
• GLP-1 injections are more suitable for patients who does not meet the criteria for surgery or patients who are not surgical candidates because of many reasons

Now systematic review has also reported efficacy and safety of GLP-1 in the treatment for patients with obesity and or T2DM after bariatric surgery

• The GLP-1 injections may be more appropriate for some patients who desire to achieve more weight loss before resorting to revision surgery straight away

Because obesity is a chronic relapsing condition

• Weight regain and return of diabetes or cardiovascular disease do occur with time
• This is normal after any types of bariatric procedures (sleeve or gastric bypass)

Hence GLP-1 injections plays an important part in the management of obesity and metabolic co-morbidities (especially T2DM) because of the incretin effect

In simple terms the mechanism of action for GLP-1 injections is the incretin response (see below for more details)

• Stimulates insulin release
• Supress glucagon secretion
• Reduce gastric emptying and increase satiety

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 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) and psychological impact (anxiety, depression, binge eating)   Inadequate weight loss is also described as suboptimal initial clinical response (SICR) Weight regain is also described as weight gain recurrence (WGR)   Unfortunately the treatment options for SICR and WGR are limited Options include: *Continue with optimization of lifestyle changes, dietitian and exercise physiologist assessment *GLP-receptor agonist or combination GIP-1/GLP-1 injections *Revision or converted bariatric procedures   The reasons for less than satisfactory response after initial surgery 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 (eg. insulin, steroids, anti depressants, etc) *Many patients already attempted intensive dietary and lifestyle interventions before bariatric surgery without satisfactory sustained clinical response *Some patients have already tried the GLP-1 injections before bariatric surgery with limited success, intolerances or affordability issues (cost prohibitive in the medium to long term) *Endoscopic procedures are rarely performed and may yield good weight loss results *Revision surgery does not guarantee success, may have side effects, follow up issues, more risk and complications   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 or dual therapy GIP-1/GLP-1 injections in our patient group described above before resorting to revision surgery *In comparison GLP-1 injections has similar weight loss outcome (10-15% TBWL) with no operative/surgical complications and less GIT side effects *GLP-1 injections have a more tailored personalized treatment with dose adjustments possible *There will be a lot more studies on GLP-1 over the next few years, the long term results, adverse events will be better reported and more information will be available

GLP-1 receptor agonist injections

GLP-1 (liraglutide, semaglutide, tirzapetide) are associated with significant weight loss for some patients with SICR after weight loss surgery

• 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

The mechanism of GLP-1 injections 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 (not so much with 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 also 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

However determining the optimal timing, duration and choice of GLP-1 therapy in post bariatric patients is critical to maximize its therapeutic benefits

• There are no current guidelines as to the dose or the administration of these injections

Most studies previously reported interval between bariatric surgery and initiation of therapy is beyond 5 years

• Recent evidence indicate that earlier administration is beneficial following 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 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

Adverse effects of GLP-1 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 baldder emptying, GLP-1 agonist have been shown to increase the risk of gallstones, acute cholecystitis and biliary obstruction With delayed gastric emptying there is a risk for pulmonary aspiration especially those within 8-12 weeks of surgery

For the Australian population

Some patients after surgery may benefit from GLP-1 agonist injections  because of 2 reasons

• Inadequate weight loss (suboptimal initial clinical response SICR)
• Weight regain with medical co-morbidities (weight gain recurrence WGR)

However these injections is costly and supply may be limited (see below)

The oral form of Semagultide is not yet available in Australia but might/will be so 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   The Therapeutic Goods Administration studied the use of high dose semaglutide 2.4mg for management of obesity in Australia (eg Wegovy)   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

Summary of clinical studies for GLP-1 before or after bariatric surgery

Randomised STEP trails compared outcomes of weekly S/C semaglutide to placebo/lifestyle modification for patients with obesity with or without diabetes

• Showed significant weight loss and 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 also indicate that GLP-1 after bariatric metabolic surgery results in additional weight loss

The GLP-1 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 to be aware of include nausea, vomiting, GIT upsets and delayed gastric emptying (less problematic after RYGBP)