Weight Loss with Tirzepatide Significantly Greater than with Semaglutide: New Data

Individuals with obesity who were treated with tirzepatide were 3 times more likely to achieve weight loss of 15% or more compared with propensity matched peers who were treated with semaglutide, according to findings of the first head-to-head comparison of weight reduction between the 2 incretin-based medications.

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The researchers reported that study participants who received tirzepatide were significantly more likely to reach weight loss of greater than 5% (1.8 times), greater than 10% (2.5 times), and greater than 15% (3.2 times) over the study period and that on-treatment changes in weight for the tirzepatide-treated group were larger at 3, 6, and 12 months of follow-up. Rates of gastrointestinal adverse effects were similar between the 2 groups, study authors wrote in JAMA Internal Medicine.

Review of clinical trial data for both medications shows that tirzepatide has produced greater weight loss among individuals with type 2 diabetes (T2D) but data from direct, real-world comparisons of tirzepatide and semaglutide in individuals with overweight or obesity have yet to be reported, researchers wrote.

For their analysis, the researchers, led by Tricia Rodriguez, PhD, MPH, principal applied scientist, Truveta Research, used a subset of data collected by Truveta, an organization that provides access to continuously updated and linked electronic health record data from a collective of US health care systems. Inclusion criteria as described in the published study required individuals to have a body weight categorized as overweight or obesity, to have received tirzepatide or semaglutide in formulations labeled for T2D from May 2022 to September 2023, to have had a baseline weight measurement available within 60 days of the first dispense of GLP-1RA, and to have no prior exposure to GLP-1 RA medications.

Rodriguez and colleagues identified the primary outcome as on-treatment weight change through November 2023. Treatment groups were balanced on measured variables using propensity scores. On treatment weight change was assessed as the likelihood of reaching 5% or greater,10% or greater, and 15% or greater reduction in body weight from baseline. Researchers also evaluated percent change in weight at 3, 6, and 12 months, according to the study.

Study follow-up continued until treatment was discontinued, a medication switch was made, or the last health care encounter or end of the study on November 3, 2023.

FINDINGS

Of an original group of 41 222 adults who met study criteria, the final cohort numbered 18 366 participants who were matched by propensity score (9193 using tirzepatide, 9192 using semaglutide). Mean age among them was 52 years, 70.5% were women, 11.8% Black, 1.9% Asian. Just over half (52.0%) were identified as having T2D. Mean baseline weight was 110 kg.

The study had a significantly high discontinuation rate. Specifically, more than half of the original participants in both the tirzepatide group (55.9%) and semaglutide group (52.5%) were not included in the final analysis.

The mean percentage change in body weight at the specified time points was significantly greater at all 3 for tirzepatide vs semaglutide (mean on-treatment follow-up of 165 days):

• 3 months: Tirzepatide -5.9%, semaglutide -3.6%
  (difference, −2.4%; 95% CI −2.5% to −2.2%)
• 6 months: tirzepatide -10.1%, semaglutide -5.8%
  (difference, −4.3%; 95% CI, −4.7% to −4.0%)
• 12 months: tirzepatide -15.3%, semaglutide, -8.3%
  (difference, −6.9%; 95% CI, −7.9% to −5.8%)

Rodriguez and colleagues found that 81.8% of participants prescribed tirzepatide lost at least 5% of their baseline weight compared with 66.5% of those prescribed semaglutide. In the tirzepatide group, 62.1% reached at least a 10% reduction in weight compared with 37.1% in the semaglutide group. Loss of 15% or more of body weight was achieved by 42.3% of tirzepatide-treated participants and by 18.1% of the semaglutide-treated group.

The likelihood of meeting the study's prescribed weight loss percentages was consistently higher for those treated with tirzepatide vs semaglutide:

• 5% HR = 1.76; 95% CI, 1.68-1.84
• 10% HR = 2.54; 95% CI, 2.37-2.73
• 15% HR = 3.24; 95% CI, 2.91-3.61

The research team noted that they observed consistent treatment effect estimates in subgroups with and without T2D, with larger weight reductions recorded among those without T2D compared with those with T2D—the underlying reasons described as “unclear.”

In a discussion of study limitations Rodriguez et al pointed to issues inherent when using clinical EHR data, including underreporting of AEs, and to reliance on brand as proxy for target dose of both medications. In addition, the study included medications labeled for T2D only. They suggested that future studies are needed to compare versions labeled for weight loss. Regarding the fact that more than half of individuals taking either drug did not complete the study, the authors noted that "additional research on discontinuation is needed, including the role of shortages, adverse events, and costs.”

"We’ve been able to compare the head-to-head effectiveness of these two important medications for weight loss in advance of smaller randomized clinical trials. This study can help to inform patient care and outcomes today, not months from now,” Rodriguez observed.

Future study is required to understand comparative effects of the 2 medications on “other key endpoints, eg, reduction in major cardiovascular events,” the authors concluded.

Source: Rodriguez PJ, Cartwright BMG, Gratzl S, et al. Semaglutide vs tirzepatide for weight loss in adults with overweight or obesity. JAMA Intern Med. Published online July 8, 2024. doi:10.1001/jamainternmed.2024.2525