VANCOUVER, Canada — Glucagon-like peptide-1 (GLP-1) agonists, like semaglutide, liraglutide, and the newly US Food and Drug Administration–approved tirzepatide, not only are gaining popularity among the public for weight loss but also are the focus of considerable attention from gastroenterology researchers.
The robust interest in GLP-1 agonists was on full display here at the American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting, with investigators sharing results on which agent is most effective for weight loss, how they compare to bariatric surgery for weight loss or prevention of metabolic dysfunction–associated steatotic liver disease, and their potential role to prevent regain after weight-loss surgery.
Head-to-Head Comparison
Tirzepatide 15 mg emerged as superior to other GLP-1 agonists for weight loss, for example, in a network meta-analysis of randomized controlled trials looking into obesity management.
Tirzepatide 15 mg was associated with the most effective mean weight loss at just over 15% when Jena Velji-Ibrahim, MD, and colleagues combined data from 14 studies with 18,714 participants with overweight or obesity but without diabetes.
Next up in order of weight-loss efficacy was tirzepatide 10 mg with 13% mean weight loss, semaglutide 2.4 mg with just over 11% mean weight loss, and tirzepatide 5 mg with almost 10% mean weight loss. The only outlier was dulaglutide 0.75 mg, which was linked to about 8% weight gain.
"While clinical trials have been conducted to assess the weight-loss efficacy of GLP-1 agonists, there has been limited head-to-head comparisons, and the data that has been obtained has been quite inconsistent," Velji-Ibrahim said when presenting results at ACG 2023.
Researchers found little difference in efficacies between tirzepatide 15 mg and 10 mg, suggesting both are a viable option for weight loss, said Velji-Ibrahim of Prisma Health Greenville Memorial Hospital and University of South Carolina School of Medicine in Greenville.
She also reported similar efficacies between oral semaglutide 50 mg and subcutaneous semaglutide 2.4 mg, "meaning that we have another option for weight management."
Side effects among the different GLP-1 agonists, and among the same agent at different doses, were not significantly different.
Comparison With Bariatric Surgery for Reducing Major Adverse Cardiovascular Events (MACE)
For many years, bariatric surgeons have pointed to the health benefits of weight-loss surgery in the right candidates, including a reduced risk for adverse cardiovascular events.
The weight loss associated with GLP-1 agonists has likewise shown benefits in reducing MACE. However, it remains unclear if one of these weight-loss strategies is better than the other in reducing these outcomes.
To determine this, researchers compared 118,828 people who had bariatric surgery to another propensity-matched group of 118,828 others prescribed GLP-1 agonists. They included adults with a body mass index (BMI) of 35 or higher in the national TriNetX database.
The multicenter, retrospective study revealed bariatric surgery was superior in reducing the risk for heart failure, MACE, and cerebrovascular disease at 3, 5, 7, and 10 years. At 10 years, for example, bariatric surgery was associated with 31% fewer composite cardiovascular events than the GLP-1 agonists.
"Our results suggest that bariatric surgery is more effective than GLP-1 analogs in preventing adverse cardiovascular events in obese patients," Ayowumi A. Adekolu, MD, an internal medicine resident at West Virginia School of Medicine in Morgantown, said in audio comments accompanying his ePoster at ACG 2023. "Although these findings highlight the benefit of bariatric surgery in mitigating adverse cardiovascular events, well-designed prospective studies are necessary to confirm these benefits in this patient population.
Possible Role in Fatty Liver Disease Prevention
In another large multicenter study from the same institution, Ethan M. Cohen, MD, along with co-author Adekolu and others, compared the effectiveness of bariatric surgery to GLP-1 agonists for preventing nonalcoholic fatty liver disease (NAFLD). Since the study was conducted, the official name of NAFLD has changed to metabolic dysfunction–associated steatotic liver disease.
Cohen and colleagues evaluated data from the TriNetX database and included adults with a BMI of 35 or higher. They propensity matched 124,022 people who had sleeve gastrectomy or Roux-en-Y gastric bypass to another 124,022 others prescribed GLP-1 agonists. Again, they looked at outcomes at 3, 5, 7, and 10 years.
They found bariatric surgery superior to GLP-1 agonists for reducing the risk of developing NAFLD. Relative risk reduction was 25% at 3 years, 28% at 5 years, 27% at 7 years, and 26% at 10 years.
Although not to the same extent as surgery in this study, GLP-1–associated weight loss did reduce risks as well.
"An important aspect of this is that for some of these people, bariatric surgery is not even an option," Cohen told Medscape Medical News, citing as an example those who do not meet the criteria for surgery.
Cohen and colleagues plan to continue the study with a larger number of participants.
Real-World Weight Regain
In another instance where a surgical procedure trumped GLP-1 agonists, revisional endoscopic sleeve gastroplasty (ESG) offered significantly higher weight loss than GLP-1 agonists among people who regained weight following initial weight-loss surgery, according to a case-control real-world study presented at ACG 2023.
"Laparoscopic sleeve gastrectomy [LSG] is a frequently performed bariatric surgery worldwide resulting in significant weight loss and improvement in obesity-related comorbidities," said Firas Bahdi, MD, gastroenterology fellow at the David Geffen School of Medicine at University of California, Los Angeles. "Despite its success, around one third of patients, unfortunately, develop weight regain warranting intervention."
Bahdi and colleagues retrospectively studied 68 adults prescribed subcutaneous semaglutide or tirzepatide after LSG, another 20 who had ESG for weight regain after LSG, and 87 controls with intact stomachs who also took GLP-1 agonists for weight loss.
They found that the ESG group experienced a significantly higher percentage of total body weight loss at 3 months than the GLP-1 group (10% vs 4.3%, respectively; P = .0001). Similarly, at the 6-month follow-up, the ESG group experienced 11.5% total body weight loss compared to 6.8% in the GLP-1 group (P = .03).
The GLP-1 after LSG group still fared better than the GLP-1 control group of people who never had surgery. Total body weight loss was 4.3% vs 5.7% at 3 months (P = .02), 6.8% vs 9.2% at 6 months (P = .02), and 9.2% vs 12.7% at 12 months (P = .03), respectively.
"In this real-world experience, revisional ESG offers significantly more weight loss than GLP-1 agonists for patients with weight regain, while also avoiding the challenges of medication refills, making it an attractive option," Bahdi said.
Future multicenter studies are warranted to confirm these results and explore physiological explanations, he added.
The study received an Outstanding Research Award in the Obesity Category (Trainee).
American College of Gastroenterology (ACG 2023). Abstracts 5, 65, P2617, and P3689. Presented October 23-25, 2023.
Velji-Ibrahim, Adekolu, Cohen, and Bahdi indicated no relevant financial relationships.
Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology, and critical care. Follow Damian on Twitter: @MedReporter.
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