Weight-Loss Showdown: Is It Time for an RCT of Bariatric Surgery vs GLP-1s?

Surgery is the gold standard, GLP-1s are all the rage—whether a head-to-head study is needed depends on who you ask.

Weight-Loss Showdown: Is It Time for an RCT of Bariatric Surgery vs GLP-1s?

Metabolic bariatric surgery is on the decline in the United States, pummeled up against the ropes by a new class of weight-loss medications favored by patients.

One recent US study reported a 25% reduction in bariatric procedures in nondiabetic patients in the last 6 months of 2022 and first 6 months of 2023. During that same time, prescriptions for glucagon-like peptide 1 (GLP-1) receptor agonists soared by more than 132%. Some surgical centers are closing because the demand for bariatric surgery isn’t there anymore.

Bariatric surgery has an established history with extensive follow-up showing durable weight loss, as well as the remission of type 2 diabetes, hypertension, and dyslipidemia, among other obesity-related diseases. GLP-1 receptor agonists, on the other hand, have delivered impressive short-term weight loss and benefits for the heart and kidneys, but the drugs don’t yet have the track record of bariatric surgery.  

“With these newer therapies, we’re getting weight loss that approaches surgery and it begs the question of whether we should compare these two directly,” Marc-Andre Cornier, MD (Medical University of South Carolina, Charleston), an endocrinologist who currently serves as president of The Obesity Society. “I think the answer is yes. I think it would be a great interest to see if we would get similar benefits, especially on clinical outcomes. I don’t think a head-to-head trial is necessary for weight loss. We know what the weight loss is with drugs and with surgery.”

In the US, bariatric or metabolic surgery is recommended for patients with a body mass index (BMI) ≥ 35 kg/m2 regardless of the presence, absence, or severity of comorbidities and for patients with obesity (BMI ≥ 30 kg/m2) and type 2 diabetes. The GLP-1 receptor agonists, including semaglutide (Wegovy; Novo Nordisk) and liraglutide (Saxenda; Novo Nordisk), also are approved for adults with obesity and for those who are overweight (BMI ≥ 27 kg/m2) with at least one weight-related comorbidity, such as hypertension, diabetes, or dyslipidemia. Tirzepatide (Zepbound; Eli Lilly), a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, is also approved for patients with overweight and obesity.

Dan Azagury, MD, chief of minimally invasive and bariatric surgery at Stanford University School of Medicine in California, agreed that a randomized study comparing the two treatments would be ideal. “There's no doubt that having a randomized trial would be the ultimate answer to all the questions,” he said. “The question is what trial would you do and what trial would be feasible.”

Several years back, Azagury, along with several colleagues, tried to launch a randomized trial comparing catheter ablation to bariatric surgery for the treatment of atrial fibrillation (AF). Since obesity is a largely modifiable risk for AF, the thinking was that surgery might be better than a procedure that doesn’t address the root cause of the arrhythmia. They’d even proposed a crossover study, one where eligible patients could undergo catheter ablation if the initial weight-loss surgery failed to treat their symptoms.

“We tried to push for that study and we even revamped it multiple times,” he said. “In the end, we had to shut down the trial, because we were never able to recruit enough patients.” 

The problem, said Azagury, is that patients came to the clinic with an idea of what they wanted in terms of treatment, which was largely the less invasive option: ablation. For weight loss, too, there are two proven strategies, but since pharmacotherapy is far less invasive, recruitment would be difficult for investigators looking to run a randomized trial.

“Scientifically, it would be great to do it, and it would be very valuable, but I think it's going to be challenging,” said Azagury, who listed other concerns as well. “One of the questions is going to be long-term maintenance. At 1 year, we know what the results are going to look like if you eliminate the question of how many people are going to come off the medications because of side effects. The interesting part is: what's the outcome going to be 5 years down the line, and ideally 10 years down the line?”

A randomized, long-term study, he said, is a “hard sell,” though it would help address some important questions, including those that revolve around not only clinical endpoints but also cost-effectiveness.

“It would not be a small undertaking,” said Cornier. That raises additional questions about funding an expensive, long-term trial. One possibility would be the US National Institutes of Health, given that the government agency funds trials of important clinical interest but limited commercial potential, he suggested.

The other scenario might see the drug companies become so confident in their medications they’d be willing to bet on a long-term head-to-head study against bariatric surgery, said Cornier.

Lots of Observational Data

There’s no shortage of randomized, controlled trials comparing metabolic bariatric surgery with lifestyle and usual care in patients with obesity and type 2 diabetes. These studies, which were conducted well before the approval of GLP-1 receptor agonists, have consistently shown that bariatric surgery leads to better short- and mid-term improvements in glycemic control, disease remission, cardiovascular risk factors, and chronic kidney disease, according to a recent review.

Data from the Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium, which is a pooled analysis from four US randomized trials conducted between 2007 and 2013, also confirmed the long-term benefits of bariatric surgery compared with a medical/lifestyle intervention.

There is no evidence from randomized, controlled trials that bariatric surgery reduces the risk of mortality or major cardiovascular events, but there are a host of observational studies and meta-analyses that consistently show an association between metabolic surgery and a lower risk of primary and secondary cardiovascular disease, particularly in people with type 2 diabetes, when compared with nonsurgical interventions or usual care.

In this regard, the new medications have a slight advantage. In the 2023 SELECT trial, A. Michael Lincoff, MD (Cleveland Clinic, OH), and colleagues showed that treatment with semaglutide reduced the risk of major cardiovascular events—a composite of CV death, nonfatal MI, and nonfatal stroke—in patients with obesity and a prior history of cardiovascular disease.

So far, there are no prospective data directly comparing the two weight-loss approaches. In one observational study of matched patients with obesity and type 2 diabetes, bariatric surgery was associated with a lower risk of mortality compared with the first-generation GLP-1 receptor agonists in patients with a diabetes duration of 10 years or less, a benefit that appeared to be mediated by via greater weight loss.

To TCTMD, Azagury pointed out that bariatric surgery in fact played a key role in understanding the effects of GLP-1 drugs: bariatric surgery increases the hormone, which in turn regulates glucose homeostasis and body weight. The magnitude of the increase in GLP-1 is larger with surgery than with drug therapy, and leads to greater weight loss, but Azagury believes that if the amount of weight loss is controlled in any head-to-head comparison, bariatric surgery and medical therapy would reduce hard clinical outcomes to a similar extent.

Maybe an RCT Isn’t Needed

Not everybody thinks a randomized, head-to-head trial is necessary at this time. Jaime Almandoz, MD (University of Texas Southwestern Medical Center, Dallas), believes that focusing on a “binary approach” to weight management is the wrong way to envision the problem. A randomized, controlled trial to work out which is best for weight loss is akin to asking whether surgery will replace chemotherapy for the treatment of cancer.

“Most bariatric surgeons are convinced that bariatric surgery is still the way to go,” said Almandoz. “They say it has the best evidence with regards to a cardiometabolic disease remission and treatment, as well as cost-effectiveness, compared to the current prices of Ozempic/Wegovy and Zepbound/Mounjaro. This does not recognize obesity as a chronic and complex disease for which neither surgery nor episodic pharmacotherapy will be curative.” 

A randomized trial might prove too difficult from an ethical perspective, added Almandoz. For example, if a patient was randomized to bariatric surgery in a long-term study, it would be unethical to simply follow those who regained weight after the procedure without offering them a GLP-1 receptor agonist or another effective obesity treatment. Cost-effectiveness studies are warranted, he said, as is research focused on identifying the patients who would be most likely to benefit from a particular treatment.

Surgeon Dana Telem, MD, MPH (University of Michigan Medical School, Ann Arbor), agreed.

“If you have a slew of highly effective options for weight loss, all with different complication profiles, the question isn't which one is better, but how do we tailor and right-size treatment to the patient?” she said. “Who would benefit from a GLP-1? Who benefits from bariatric surgery? How do we augment or use either neoadjuvant or adjuvant therapy perhaps for persons with higher BMI who've had surgery? The wrong question is an either-or question. The right question is around the optimization of the various treatments.”

If you have a slew of highly effective options for weight loss, all with different complication profiles, the question isn't which one is better, but how do we tailor and right-size treatment to the patient? Dana Telem

The Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the most frequently performed procedures, and successful surgery is defined as at least a 50% reduction in excess weight that is sustained for 5 years. Regaining weight after surgery is not uncommon, though. In one recent review, half of patients regained at least 10% of the maximum weight lost (or experienced a 4- or 5-point increase in BMI), with the prevalence of weight regain higher with RYGB.

Weight lost and regained with new GLP-1 receptor agonists has also become much clearer as evidence accumulates. While weight loss tends to range from 15% to 20% with the GLP-1 receptor agonists, when patients stop taking the medications, they regain the weight—a phenomenon making headlines in the mainstream media. In the STEP 1 extension study, patients gained back two-thirds of the weight initially lost with semaglutide and also experienced a worsening of multiple cardiometabolic risk factors. Similar weight regain has been seen with tirzepatide.

How to Decide on Treatment?

Without randomized data, Telem said, there are a number of factors that impact treatment choice, not all of which, unfortunately, are related to the patient’s clinical profile.

Access to the medications, cost, and tolerability are some of the major issues limiting the use of GLP-1 receptor agonists. Blue Cross Blue Shield of Michigan, for example, no longer covers the drug class in its fully insured plans as of 2025 because of the high cost of treatments. Some seniors may soon get a break on costs, with Ozempic and Wegovy among the 15 drugs most recently targeted for Medicare price negotiation, as announced by the US Department of Health and Human Services last week. Even when patients can get the drugs and afford them, however, not everybody can stay on them. In the SELECT trial, for example, nearly 17% of patients stopped taking the medication during the study period, with gastrointestinal side effects the most common reason for doing so. Other studies have suggested that nearly half of patients stop taking the drugs in the first year.  

“Obviously, as a bariatric surgeon I'm biased, but I still think that a therapy that is—I don't want to say ‘one and done’ because it's never done—a one-time treatment with good outcomes is better than having to take shots every couple of weeks. But not everybody feels that way,” said Telem.

Even with the current best available therapies, procedural or medical, they aren’t curative and we need to integrate and individualize our approaches to obesity treatment. Jaime Almandoz

Cornier said patient preference is a major factor, adding that some have simply decided they don’t want surgery while others are adamantly against a lifetime of medication. “We try to educate patients,” he said. “Generally, for someone to be a candidate for surgery, they have to have had failed diet, but they don’t have to have had failed medical therapy. In my mind, we might want to try medical therapy first if we can, but many insurers will cover surgery but not medical therapy.”

Almandoz said the conversation with patients looks different depending on the clinical practice. As the director of a weight-management program at an academic medical center, he is referred patients with severe end-organ damage or complicated/advanced type 2 diabetes. Some have not been listed for organ transplantation because their BMI is too high or they may be a breast-cancer survivor referred from oncology with the goal of losing weight to improve their chance of disease-free survival.

“These patients are referred for to us for weight loss to improve specific health goals,” said Almandoz. While the conversation often gets simplified as “losing weight,” the primary objectives should be improvements in health and quality of life. Any future study needs to account for these metrics, he said.

Almandoz stressed that obesity is a chronic disease that demands long-term, not episodic care. Patients, he noted, are often disparaged as lacking willpower when they gain weight back after stopping the medication, or if there’s weight regain following bariatric surgery, but the field is shifting in many centers to think about obesity management in a more systematic way.

“We're realizing people with obesity will likely need lifelong obesity care to manage their weight and health risks. Even with the current best available therapies, procedural or medical, they aren’t curative and we need to integrate and individualize our approaches to obesity treatment,” he said.

Azagury said weight-management centers would ideally provide patients with both options, noting that treatment often evolves with all chronic diseases.

“The expectation is we're going to need to tweak things over time,” he said. “We have patients who come back after a year, year-and-a-half, or whatever, and say, ‘Hey, I lost 30 pounds on this drug. I feel great, I'm very happy, but I don't want to keep taking it forever or I worry that my insurance is going to pull the plug. What are my options?’ We also have some patients who have had surgery years or decades ago who are struggling a little bit more with their weight loss and want to know their options, too. There's a lot of ongoing conversation with patients about going from one treatment to the other.”

Telem said there are surgeons becoming certified in obesity medicine so they can have comprehensive conversations with patients. This allows them to take ownership of the management and prescription of weight-loss medications in the context of a multidisciplinary program. And while there has been a decrease in bariatric procedures, volume has never been massive, she said, noting that less than 1% of eligible patients undergo bariatric surgery.

While some centers may close, the highly reputable programs will continue to prosper, she predicted. “There’s plenty of room for everybody in this space.”  

Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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Disclosures
  • Cornier, Azagury, and Telem report no conflicts of interest.
  • Almandoz has previously reported consulting fees from Boehringer Ingelheim, Eli Lilly and Company, and Novo Nordisk A/S.

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