Although the tide of therapies targeting glucagon-like peptide receptor agonists (GLP-1 RA) – like semaglutide, and di- and triagonists, like tirzepatide and retatrutide – marks a breakthrough in obesity treatment and is revolutionising healthcare, several questions remain regarding how clinicians should integrate these medications into clinical practice.
In a viewpoint published online in JAMA Surgery, surgeons Jason Samuels, Mayur Patel, and Kevin Niswender write that key considerations include delineating ideal treatment objectives, establishing criteria for non-response, and formulating strategies for combination therapy protocols.
They write:
Bariatric surgery, the primary treatment for class 2 or 3 obesity, is among the safest surgical procedures in the US, with extensive long-term data demonstrating sustained efficacy across diverse populations.
Meanwhile, GLP-1 RA therapies are approaching the effectiveness achieved with surgery. The phase 3 trials of GLP-1–based therapies underscore their efficacy, resulting in weight loss of up to 25% within one year of treatment.
As a result, an opportunity exists to implement a more personalised approach to obesity treatment through a comprehensive multi-disciplinary evaluation that considers surgical, medical, and combined therapies, ultimately leading to improved and durable outcomes.
The first significant hurdle to implementing harmonised surgical and medical treatment programmes is the absence of harmonised ideal treatment objectives.
This creates challenges in assessing the effects of a specific therapy on a patient’s health and in designing clear treatment targets for assessing efficacy in trials of combined therapies.
Treatments for obesity currently centre on weight management using body mass index (BMI) as a reference point.
However, the concept of a singular “healthy” BMI is questioned, as the risks for comorbid disease development with obesity varies across ethnic sub-populations. For example, individuals of Asian descent are more likely to develop diabetes at a lower BMI compared with white patients.
Despite this, clinicians lack population-specific targets for obesity treatment. In fact, the American Medical Association recently raised concern with the utility of BMI as a measure of health, but no clear replacement for BMI exists.
Possible substitutes include indicators of central adipose accumulation, like waist circumference, measurements of adipose and lean body mass, or biomarkers that indicate metabolic irregularities.
To date, few studies have explored the predictive ability of altering these markers of adiposity and the rate of comorbid disease remission. In this new environment in which dramatically more weight loss is achievable, these prevailing uncertainties surrounding treatment targets for obesity create a landscape in which interpreting outcomes is a formidable challenge.
Equally imperative to defining treatment objectives for obesity, we must determine how to define criteria for non-response.
The STEP 4 and SURMOUNT-4 trials demonstrated the impact of therapy discontinuation, with significant weight regain in patients randomised to treatment termination.
These findings suggest that drug intolerance and discontinuation will lead to weight regain. Likewise, the surgical literature has repeatedly found significant variation in the clinical response to bariatric surgery.
Despite this, to our knowledge, no prospective trials have evaluated how best to augment weight loss in surgical patients with clinical non-response.
This issue also exists for patients experiencing the separate phenomenon of weight regain, occurring in 35% to 75% of patients who undergo bariatric surgery.
Compounding these challenges, obesity treatment often revolves around an either/or approach, compelling patients to choose between medical or surgical weight loss.
Once either medical or surgical weight loss is chosen and therapy starts, the absence of clear definitions for clinical nonresponse and pathways for rescue therapies exacerbates the incongruity between these unnecessarily segregated treatment modalities.
This ambiguity is likely to contribute to the inadequate follow-up across medical and surgical weight loss programmes as patients become disenfranchised with their obesity care.
To pave the way for evidence-based outcomes in obesity treatment, a holistic paradigm shift is essential. Similar to multidisciplinary oncology clinics and the management of gastro-oesophageal reflux, patients should be assessed with consideration for all available obesity therapies – medical, endoscopic, psychosocial, and surgical.
Continual reassessment of disease response is crucial, with new therapies introduced as needed to achieve clinical goals. On achieving disease remission, strategies for ongoing monitoring and prevention of obesity recurrence must be integrated into treatment plans.
These decisions should occur with considerations toward patient-focused goals and cost-effectiveness in mind. Hence, the choice between surgical, medical, or combined approaches necessitates a judicious balance of disease-focused treatment escalation and de-escalation, guided by individual patient goals, the availability of health care resources, payer support, and the evidence supporting each therapeutic option.
Samuels, Patel and Niswender are with the Department of Surgery, Vanderbilt University Medical Centre, Nashville, Tennessee.
JAMA Network Step 4 trial (Open access)
JAMA Network SURMOUNT 4 trial (Open access)
JAMA Surgery article – Time to Rethink the Approach to Treating Obesity (Open access)
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