Tirzepatide outperforms semaglutide for weight loss

Adults with overweight or obesity receiving tirzepatide experienced greater weight loss than those treated with semaglutide, according to a large U.S. cohort study published in JAMA Internal Medicine.

“We found that patients receiving tirzepatide were significantly more likely to achieve clinically meaningful weight loss thresholds and experienced greater reductions in body weight over time,” said Brianna Cartwright, MS, principal research analyst and lead for Truveta Research at Truveta.

Researchers conducted a retrospective cohort study using electronic health record data linked to medication-dispensing information from a collective of U.S. health systems through the Truveta database. Eligible patients were adults with overweight or obesity who initiated tirzepatide or semaglutide formulations approved for type 2 diabetes and had no prior exposure to glucagon-like peptide-1 receptor agonist therapy.

The real-world analysis evaluated adults treated between May 2022 and September 2023 and found that patients receiving tirzepatide were more likely to achieve clinically meaningful weight loss and experienced larger reductions in body weight at 3, 6, and 12 months of treatment.

The primary analysis used 1:1 propensity score matching that included 18,386 patients drawn from an initial cohort of 41,222 patients. The mean age was 52 years, 71% were female, and 52% had type 2 diabetes. Mean baseline weight was 110 kilograms.

Within one year of treatment, patients receiving tirzepatide were more likely to reach clinically meaningful weight-loss milestones than those receiving semaglutide. Rates of ≥5%, ≥10%, and ≥15% weight loss were 82%, 62%, and 42% with tirzepatide compared with 67%, 37%, and 18% with semaglutide.

Average weight loss also favored tirzepatide at all evaluated time points. Mean percentage weight reduction was −5.9% versus −3.6% at three months, −10.1% versus −5.8% at six months, and −15.3% versus −8.3% at twelve months.

“These findings reinforce a consistent trend we are seeing across both clinical trials and real-world data,” Cartwright said. “Tirzepatide-based medications consistently outperform semaglutide-based medications for weight loss in patients with overweight or obesity.”

Stratified analyses showed larger reductions in body weight among patients without type 2 diabetes compared with those with diabetes, though the relative advantage of tirzepatide remained consistent across groups.

Rates of moderate to severe gastrointestinal adverse events — including bowel obstruction, cholecystitis, cholelithiasis, gastroenteritis, gastroparesis, and pancreatitis — were similar between treatment groups. Because adverse events were captured through electronic health record data, milder or unreported symptoms may not have been fully captured.

Treatment discontinuation was common in real-world practice, with follow-up ending because of discontinuation for 56% of patients receiving tirzepatide and 53% receiving semaglutide within one year. Such discontinuation rates may influence how clinicians interpret longer-term effectiveness outside controlled clinical trials.

“In addition to effectiveness, medication availability and insurance coverage will likely play a role in deciding which medication to initiate,” Cartwright said. “Providers should evaluate these findings alongside those considerations as they determine which option may be best for individual patients.”

The researchers noted several limitations typical of observational studies using clinical data. Weight measurements depended on routine clinical visits, adverse events may be underreported in electronic health records, and unmeasured confounding — such as differences in patient motivation for weight loss — may influence results.

The analysis also relied on medications approved for type 2 diabetes rather than formulations specifically approved for obesity, and the geographic distribution of participating health systems was not nationally representative.

Still, the consistency of findings across analytic approaches suggests that dual incretin therapy may produce greater weight reduction than GLP-1 receptor agonist therapy alone in routine clinical practice.

“Clinicians can use these data alongside clinical trial evidence when discussing treatment options with patients,” Cartwright said.

An outside expert said the findings should be interpreted within the broader clinical context of metabolic disease management.

“The emerging data do suggest greater weight loss with tirzepatide compared with semaglutide, but gastroenterologists should interpret these results in the broader context of patient-specific factors such as metabolic risk, tolerability, cost (including insurance coverage), and long-term adherence,” said Jessica E. S. Shay, MD, PhD, assistant professor of medicine in the division of gastroenterology, hepatology and nutrition at the University of Utah in Salt Lake City.

Dr. Shay, a hepatologist who specializes in metabolic liver diseases including metabolic dysfunction–associated steatotic liver disease (MASLD) and metabolic dysfunction–associated steatohepatitis (MASH), noted that clinicians should consider these agents as part of a broader strategy for managing metabolic disease.

“This is an exciting time for our patients, as we are now in an era where multiple effective agents are FDA approved and several more are in late-phase clinical trials. For patients with obesity-related GI conditions such as MASLD, these medications are best viewed as part of a broader strategy for managing metabolic disease rather than choosing between them based on weight loss alone, particularly as longer-term safety and outcomes data continue to evolve.”

Further research will help clarify long-term comparative effectiveness and patterns of medication persistence in routine care.

Disclosures: One author reported consulting fees from Premier outside the submitted work; no other conflicts of interest were reported.

Source: JAMA Internal Medicine

 Key Takeaways

• Tirzepatide produced greater weight loss than semaglutide in a large real-world cohort analysis.
  • Patients receiving tirzepatide were 1.8× more likely to achieve ≥5% weight loss, 2.5× more likely to achieve ≥10%, and 3.2× more likely to achieve ≥15%.
  • Mean weight loss approached 15% at one year with tirzepatide, compared with about 8% with semaglutide.
  • Moderate to severe gastrointestinal adverse event rates were similar between medications.
  • Treatment discontinuation exceeded 50% within one year, highlighting adherence challenges in real-world care.