Glucagon-like peptide 1 receptor agonists make up a new class of weight loss drugs expected to change the face of obesity management. These repurposed diabetes medications, including semaglutide and tirzepatide, have surged in popularity since the first was approved in 2021 for long-term weight management.
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“The impact of these anti-obesity medications is undeniable,” says Raul J. Rosenthal, MD,FASMBS, a past president of the American Society of Metabolic & Bariatric Surgery (ASMBS), noting that bariatric surgery consults are down 30% nationwide in the past year. “They have the potential to dramatically change how we address the obesity epidemic.”
The American Medical Association (AMA) recognized obesity as a disease just over a decade ago. It is a condition that affects about 42% of the U.S. adult population and has many contributing factors, including genetic, physiological, environmental and social. It also has been linked to more than 220 medical conditions, notably type 2 diabetes, cardiovascular disease, liver disease and many cancers.
“Obesity is a complex disease that requires a range of treatment and prevention options,” says Dr. Rosenthal, who serves as Regional Chair of the Digestive Disease Institute for Cleveland Clinic in Florida and Director of The Bariatric & Metabolic Institute at Cleveland Clinic Weston Hospital. “That’s why I see weight loss medications as a complement to bariatric surgery. It’s another tool in the toolbox.”
While weight loss drugs have been around for years, the new batch of GLP-1 receptor agonists, which include Wegovy (semaglutide) and Zepbound (tirzepatide), are making headlines every day. These medications are prescribed for chronic weight management in adults who have obesity or those who are overweight with a co-morbidity, like high blood pressure or high cholesterol.
“These medications have been shown to help patients lose 15% to 20% of their body weight,” says Dr. Rosenthal. “In comparison, patients typically lose 20% to 35% of their body weight with surgery.”
The active ingredients in these injectable anti-obesity medications were originally used for treating type 2 diabetes: Ozempic (semaglutide) and Mounjaro (tirzepatide). They work by mimicking a hormone that slows gastric emptying, decreases a person’s appetite, and helps improve glycemic control.
“All these medications are meant to be used alongside lifestyle modifications, which remain the bedrock for treating obesity,” stresses Dr. Rosenthal.
Growing understanding about the chronic nature of obesity indicates long-term management is necessary for patients to maintain their weight loss. But research, including the SURMOUNT-4 trial and the STEP 1 trial extension, has shown that patients experience weight regain once they stop taking these medications.
“Like high blood pressure or cholesterol, the numbers come down with the drugs and go back up without them,” says Dr. Rosenthal. “Adherence is key to their effectiveness.”
A retrospective cohort study conducted by Cleveland Clinic researchers, however, found that a majority of patients discontinue their use of anti-obesity medication after only a few months. Patients receiving semaglutide had the longest adherence with 40% persistent at 1 year.
Concerns over side effects and cost bring into question whether GLP-1 agonists will be a sustainable solution for individuals requiring life-long treatment.
Common gastrointestinal side effects associated with these drugs include nausea, vomiting, constipation, and diarrhea. But research has linked GLP-1 agonists to serious digestive problems such as gastroparesis, pancreatitis and intestinal obstructions. In addition, the FDA has recently identified potential safety issues based on reports of other rare non-GI side effects, such as hair loss and suicidal ideation.
Drug pricing also has raised compliance concerns. Patients typically pay more than $1,000 a month for these prescriptions, which are often not covered by insurance. Dr. Rosenthal fears this lack of affordability will push open the door to greater healthcare disparity.
Meanwhile, as many payers and employers face coverage decisions concerning anti-obesity medications, some health insurance companies are easing access to bariatric surgery. According to industry reports, some are eliminating prior authorization requirements and covering bariatric surgery for more conditions.
“This is not altogether surprising when you consider two years of weight loss medications are comparable in cost to having bariatric surgery,” says Dr. Rosenthal.
Bariatric surgery is currently the most effective treatment for obesity. It’s also a long-term treatment option, notes Dr. Rosenthal. “Less than a third of our patients experience weight regain following surgery,” he says.
Approximately 228,000 individuals receive bariatric surgery in the United States each year. Laparoscopic sleeve gastrectomy is the most common surgery, accounting for about 70% of cases. It entails removing a large portion of the patient’s stomach to limit food intake. The procedure also reduces hunger hormones — ghrelin and leptin — that are produced in the stomach.
“Despite its efficacy, just 1% of the affected population undergoes surgical treatment for obesity, and that number may go down, at least temporarily, as more people opt for new weight loss medications,” states Dr. Rosenthal.
The eligible population was recently expanded when the American Society for Metabolic and Bariatric Surgery updated its clinical guidelines for metabolic and bariatric surgery in 2022. In addition to individuals with class 3 or severe obesity (BMI ≥40 kg/m2), surgery is now recommended for individuals with class 2 obesity (BMI ≥35 kg/m2) alone as well as individuals with diabetes and class 1 obesity (BMI 30-34.9 kg/m2). The guidelines also recommend surgery for patients with class 1 obesity and other comorbidities who do not achieve substantial or durable weight loss using nonsurgical methods.
“We now offer GLP-1 agonists as a nonsurgical option for patients who are not eligible for weight loss surgery,” says Dr. Rosenthal. “These medications also can be useful for patients following surgery who have weight regain or who are not able to attain their target weight.”
The benefits of both bariatric surgery and anti-obesity medications extend beyond weight loss.
Multiple studies have demonstrated a significantly lower risk of incident major adverse cardiovascular events (MACE) following bariatric surgery, including a retrospective cohort study led by Cleveland Clinic researchers and published in JAMA in 2019.
More recently, a Cleveland Clinic study co-authored by Dr. Rosenthal also found that bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality among adults with obesity. The SPLENDID matched cohort study included 5,053 adult patients with obesity who underwent bariatric surgery at Cleveland Clinic hospitals in Florida and Ohio and 25,265 patients who received usual care without surgery.
“We observed a dose-dependent response between weight loss in patients who underwent surgery and the incidence of cancer,” says Dr. Rosenthal. He emphasizes the importance of this treatment benefit in light of a 2017 report that linked obesity and overweight to 40% of cancers diagnosed in the United States.
Studies published last year found that GLP-1 agonists also demonstrate cardiovascular benefits. Results from the SELECT trial presented at the American Heart Association’s Scientific Sessions 2023 in November show that among 17,000 people with overweight or obesity and cardiovascular disease, those taking semaglutide had a 20% lower risk of heart attacks and strokes than those on placebo.
Another trial, published the New England Journal of Medicine in August 2023, found semaglutide significantly reduced symptoms and improved quality of life in people with obesity and heart failure with preserved ejection fraction.
“When it comes to managing a chronic, relapsing disease like obesity, there is no one size fits all and that won’t change with time,” asserts Dr. Rosenthal. He points to Cleveland Clinic in Florida’s use of bariatric surgery as a bridge to organ transplantation and its ability to achieve rapid weight loss for critically ill patients, as an example of how each patient requires a personalized approach.
He also acknowledges that weight loss medications have the potential to be a less costly, more accessible way to address obesity and obesity-related conditions in the future, but it’s a work in progress. “A more affordable, non-injectable form of a GLP-1 agonist that can help patients achieve significant weight loss would be a true game changer,” he adds.
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