TOPLINE: 

In matched real-world cohorts, tirzepatide was associated with greater and faster weight loss and lower rates of gastrointestinal and systemic adverse events than semaglutide. With both medications, women and White patients more frequently achieved high weight loss responses, whereas men, Black patients, and Hispanic patients had minimal weight loss.

METHODOLOGY:

• GLP-1 receptor agonists have transformed obesity treatment, but real-world weight loss responses vary widely and aren’t completely understood.
• Researchers conducted a retrospective cohort study using de-identified electronic health records from US academic medical centers. They first identified patients with at least one order for a GLP-1 and then restricted the analysis to those with at least three semaglutide or tirzepatide prescriptions over at least 1 month; 10,339 tirzepatide-treated and 10,339 semaglutide-treated patients were included after propensity matching for age, sex, and other baseline factors.
• Patients were categorized into five response groups based on maximum weight loss over 2 years: those with high response (> 15% weight loss), moderate response (5%-15% weight loss), late response (< 5% weight loss in year 1 and > 5% weight loss in year 2), weight regain (> 5% weight loss in year 1 and ≥ 5% regain in year 2), or minimal weight loss (< 5% weight loss).
• Rates of adverse events were compared between the propensity-matched semaglutide and tirzepatide groups within each weight loss response category by analyzing 16 common adverse events listed in FDA prescribing information and identified from unstructured clinical notes during the 2-year follow-up.
• Researchers also compared weight loss trajectories, demographic patterns, and pre- to posttreatment changes in disease prevalence between the two drugs during the follow-up period.

TAKEAWAY:

• Patients treated with tirzepatide achieved a mean maximum weight reduction of 14.7% (16.0 kg), whereas those treated with semaglutide achieved a mean maximum weight reduction of 10.8% (11.6 kg) over 2 years (P < .001). Tirzepatide treatment was also associated with greater weight loss than semaglutide treatment at every threshold, with more patients achieving at least 5%, 10%, 15%, 20%, and 25 % body weight reductions.
• In the high-response group, tirzepatide was associated with a faster mean monthly rate of weight loss than semaglutide during the first 6 months after treatment initiation (2.54% vs 2.18%; P < .001).
• Patients treated with tirzepatide in the high-response group had a lower posttreatment prevalence of multiple gastrointestinal adverse events, including nausea (27.2% vs 31.4%; P = .002), vomiting (12.8% vs 17.1%; P < .001), constipation (16.9% vs 20.2%; P = .005), and diarrhea (16.9% vs 19.2%; P = .04), than those treated with semaglutide.
• Weight loss response distributions by race, ethnicity, and sex showed that White patients were more represented in the high-response group than in the minimal-response group for both semaglutide and tirzepatide, whereas Black and Hispanic patients were more represented in the minimal-response group. Additionally, women were more represented in the high-response group for both drugs.

IN PRACTICE:

“Tirzepatide was associated with greater and faster weight loss, lower adverse-event prevalence, and larger reductions in multiple disease burdens compared with semaglutide, while both agents produced meaningful improvements across metabolic, respiratory, and neuropsychiatric domains,” the authors wrote. “The wide spectrum of outcomes and demographic gradients observed emphasize the urgent need for precision approaches to obesity treatment and highlight opportunities for next generation incretin therapeutics informed by real-world response phenotypes.”

SOURCE:

The study was led by A. J. Venkatakrishnan and Karthik Murugadoss, Metabolism Agentic Intelligence Atlas in Cambridge, Massachusetts. It was published online on in PNAS Nexus.

LIMITATIONS:

Because this was a retrospective observational study, the results may still be affected by hidden confounding and bias. The study also did not track dose increases, highest dose reached, or how long people stayed on treatment, even though these can affect weight loss. In addition, weight loss and side effects were measured separately, but they are probably connected in real-world care, so it is hard to tell which caused which.

DISCLOSURES:

The authors are employees of nference Inc, which conducts research collaborations with various biopharmaceutical companies, including Eli Lilly and Company and Novo Nordisk A/S, whose GLP-1 receptor agonist products (semaglutide and tirzepatide) are included in this study. 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.