Real-world Patients Might Lose More Weight With Tirzepatide vs Semaglutide

With CV outcomes data still pending for tirzepatide, this study may not impact current drug choices if other factors are at play.

Real-world Patients Might Lose More Weight With Tirzepatide vs Semaglutide

In a real-world population of adults with overweight or obesity, use of tirzepatide more often resulted in clinically meaningful weight loss, as well as a larger magnitude of weight reduction, than did semaglutide out to 12 months.

The findings were maintained regardless of diabetes status, and there were no differences observed in the rates of gastrointestinal adverse events between the drugs. Notably, the study, published online this week in JAMA Internal Medicine, did not report cardiovascular endpoints. Previously, the SELECT trial showed an advantage in cardiovascular outcomes with semaglutide, but nothing yet has been published regarding any cardiovascular benefits of tirzepatide.

“The most important takeaway is that the majority of patients on both drugs experience clinically meaningful weight loss, which is generally defined as 5% or more,” lead author Patricia Rodriguez, PhD (Truveta, Bellevue, WA), told TCTMD. “While tirzepatide was consistently more effective than semaglutide on a variety of weight-related endpoints, both medications are effective, and there are a variety of other factors that patients will want to consider when they're thinking about this, including the important factor related to access and insurance coverage, which might mean that one is available and the other isn't.”

“Right now, both of these drugs, of course, are in relatively short supply, costs are of consideration, and different insurances may have different formulary preferences,” echoed A. Michael Lincoff, MD (Cleveland Clinic, OH), who served as the study chair for SELECT. “There are a lot of factors that would govern the choice of these drugs beyond the relative effects on weight,” he commented to TCTMD, “but I think this [study] may just make it more apparent . . .  that in terms of pure weight reduction, tirzepatide appears to have more effect.”

Still, because of the lack of data showing any kind of cardiovascular benefit with tirzepatide, he said he would prefer to prescribe semaglutide for patients with any CVD. “I don't think we can necessarily extrapolate body weight changes to cardiovascular outcomes,” Lincoff added.

Tirzepatide vs Semaglutide

Both tirzepatide and semaglutide are part of the new class of injectable glucagon-like peptide-1 (GLP-1) receptor agonists, however the former also activates the hormone glucose-dependent insulinotropic polypeptide (GIP). GLP-1 affects satiety and gastric emptying, while GIP helps control regulation and storage of adipose tissue.

For their study, Rodriguez and colleagues included Truveta electronic health record (EHR) data for 41,222 patients (mean age 55.4 years; 66.8% female) with overweight or obesity who were newly prescribed semaglutide (n = 32,029) or tirzepatide (n = 9,193) between May 2022 and September 2023. Mean duration of follow-up was 165 days, and just over half of each group discontinued their medication during the study period. There was a lower prevalence of type 2 diabetes in the tirzepatide group than in the semaglutide group (51.9% vs 71.5%).

After propensity-score matching, baseline characteristics were well balanced between the two groups, and more patients taking tirzepatide lost weight compared with semaglutide by 1 year.

Weight Loss at 365 Days




HR (95% CI)

≥ 5% Loss



1.76 (1.68-1.84)

≥ 10% Loss



2.54 (2.37-2.73)

≥ 15% Loss



3.24 (2.91-3.61)

Additionally, after adjustment for residual confounders, the mean on-treatment change in body weight was 2.4%, 4.3%, and 6.9% lower for tirzepatide compared with semaglutide at 3, 6, and 12 months, respectively.

Subgroup analyses by diabetes status maintained the study findings but showed that patients without diabetes lost more weight than those with the disease.

Lastly, the researchers noted no differences in reported moderate-to-severe gastrointestinal adverse events between the drugs. However, Rodriguez noted they did not include mild side effects like nausea and vomiting, which are often seen with this class of medications.

At the time of the study, the US Food and Drug Administration had cleared the two drugs, as Mounjaro (Eli Lilly) and Wegovy (Novo Nordisk), respectively, only for use in patients with diabetes. Subsequently, both were approved for weight loss in patients with overweight and obesity, this time under the names of Zepbound and Ozempic. Semaglutide, marketed as Wegovy, also has the agency’s signoff in CVD patients with overweight or obesity as a means of reducing the risk of cardiovascular death, MI, and stroke.

‘Fairly Representative’

For Rodriguez, the biggest strength of their findings is that they did not include pharmacy claims, but rather EHR data, which allowed them to also patients who may have paid out of pocket, she said. “As far as we understand, a lot of patients are taking these medications off-label, [and] a lot of those patients wouldn't have this paid for by insurance. So, we do think it’s fairly representative.”

Still, more data are needed. “Our hope is that this will inspire other researchers to build upon this study,” Rodriguez said, noting that the cardiovascular outcomes component is the largest missing piece. “This is really just a first step in understanding these medications.”

For Lincoff, the new results are “interesting,” but he cautioned that further head-to-head comparisons of the drugs using “uncontrolled” information sourced from databases might not offer much more than what is already known from trials. Should either semaglutide or tirzepatide become standard of care in the future, especially for CVD patients, Lincoff said, then “it will be more relevant in the future for trials to have active controls.”

  • Rodriguez reports no relevant conflicts of interest.
  • Lincoff reports serving as a consultant for and receiving research support from Novo Nordisk and Eli Lilly.