Tirzepatide Is the Preferred GLP-1 Agonist for Weight Loss, Meta-Analysis Suggests

Jena Velji-Ibrahim, MD, MSc

Prisma Health Greenville Memorial Hospital

University of South Carolina School of Medicine

Tirzepatide at 15 mg was the most efficacious GLP-1 agonist for obesity management in patients without diabetes, according to a systemic review of data from the MEDLINE and Embase databases that was presented at the American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting in Vancouver, Canada.¹

In the analysis, the efficacy of each GLP-1 agonist compared with placebo was ranked using rankogram, with 15-mg tirzepatide given a 98% chance of being the most effective preferred treatment. Tirzepatide 10-mg was ranked 89%, with semaglutide 2.4 mg and 5-mg tirzepatide both ranked at a 65% likelihood of being the best treatment. Oral semaglutide 50-mg was ranked 54% and semaglutide at a dose below 2.4 mg was at 41%.

"Current guidelines do recommend these agents in BMI greater than 30 but very few patients are on a GLP-1 agonist, and that needs to increase. We need to prescribe them more," lead investigator Jena Velji-Ibrahim, MD, MSc, Prisma Health Greenville Memorial Hospital, University of South Carolina School of Medicine, said during her presentation. "I think depending on the patient, we have several options. Whether you use it first depends on the patient and what they want to do but we need to remember that we have these medications in our back pocket to use."

The FDA has approved 2 GLP-1 agonists for the treatment of patients with obesity, specifically a body mass index (BMI) of 30 kg/m2 or higher. These agents include liraglutide (Saxenda), which was approved in 2014, and semaglutide (Wegovy), which gained approval in 2021. A third agent, tirzepatide, is currently being considered by the FDA for a potential approval in obesity management. This agent has a dual mechanism of action targeting GIP and GLP-1, making it potentially unique from the other treatments. Lilly, the company that develops tirzepatide, expects a decision from the FDA as early as the end of 2023.²

The analysis presented at ACG examined data from 17 randomized controlled trials that explored various GLP-1 agonists across 22,000 adult patients. Patients examined for the analysis had a BMI of ≥30 or ≥27 kg/m² with obesity related comorbidities. Patients for the analysis had received the treatment for 40 weeks or more and changes in body weight must have been measured as a primary or secondary end point.

Across the study, tirzepatide at any dose was the most effect for reducing body weight compared with placebo. In the study, tirzepatide at 5 mg was found to induce a -13.60% reduction in weight (95% CI, -15.48 to -11.72), the 10 mg dose resulted in a mean -19.00% change in weight (95% CI, -20.88 to -17.12). The 15 mg dose, which was found to have the highest level of weight change, induced a -20.10% change in body weight (95% CI, -21.98 to -18.22). Comparisons were also produced between the arms, with tirzepatide 15 mg superior to all except to the tirzepatide 10 mg dose (-1.10 difference; 95% CI, -2.98-0.78).

The second most effective agent for weight management was semaglutide 2.4 mg, which induced a mean change in body weight of -13.61% (95% CI, -15.33 to -11.89). For those receiving a semaglutide dose of less than 2.4 mg, the mean change in weight was -11.18% (95% CI, -13.57 to -8.79). Oral semaglutide, which is delivered at 50 mg, resulted in a -12.70% change in weight (95% CI, -14.74 to -10.66). On the comparison, all 3 doses of semaglutide were like each and also to the 5 mg dose of tirzepatide.

"When comparing subcutaneous to oral, there was not a significant difference between weight loss, so any formulation resulted in a weight loss," said Velji-Ibrahim.

Although some weight change was observed, the least effective GLP-1 examined was liraglutide. At the 3 mg dose, liraglutide induced a -4.79% change in body weight (95% CI, -5.74 to -3.84). At the 1.8 mg dose, liraglutide reduced body weight by -3.78% (95% CI, -6.73 to -0.84).

In an assessment of adverse event (AE), gastrointestinal AEs were more common with the GLP-1 agents compared with placebo. The odds ratio for GI AEs were 4.86 and 4.72 for semaglutide 25 mg and 50 mg. For tirzepatide 5 mg and 15 mg the odds ratios were 4.76 and 6.27. Rates of pancreatitis were similar with the GLP-1 agents to placebo, with odds ratios around 1 and not statistically significantly different. For serious AEs, there also was not a meaningful difference compared with placebo.

"There's not really a significant difference between them and doses," said Velji-Ibrahim. "GLP-1 agonists were not associated with pancreatitis compared with placebo."

References

1. ^{Velji-Ibrahim J, Radadiya D, Devani K, et al. GLP-1 Agonists and their Efficacy for Weight Loss: Unraveling the Best Option through Network Meta-Analysis. Presented at: ACG 2023 Annual Meeting; October 20-25, 2023. Abstract 5.}
2. ^{Lilly's tirzepatide achieved up to 15.7% weight loss in adults with obesity or overweight and type 2 diabetes in SURMOUNT-2. News release. Eli Lilly and Company. April 27, 2023. Accessed October 23, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-achieved-157-weight-loss-adults-obesity-or}