Tirzepatide Outperforms Semaglutide on Combined T2D Goals

Patients treated with tirzepatide have a significantly increased likelihood of attaining combined key therapeutic targets in the control of type 2 diabetes (T2D) compared with semaglutide, a post hoc analysis of the phase 3 SURPASS-2 trial showed. 

“In this post hoc analysis, we showed that tirzepatide was superior to semaglutide in achieving standard and intensive goals in type 2 diabetes control,” said first author Ana Rita Leite, MD, of the Department of Endocrinology, Diabetes, and Metabolism, São João Local Health Unit, Porto, Portugal, in presenting the findings at ENDO 2025: The Endocrine Society Annual Meeting.

“All doses of tirzepatide were superior in achieving these goals compared with semaglutide 1 mg, and there was a dose-dependent increase in the number of therapeutic goals attained with higher doses of tirzepatide,” she said.

While the advent of GLP-1 receptor agonist drugs has helped transform the management of T2D, patients often achieve only partial improvement in the spectrum of important outcomes.

“Simultaneous control of hyperglycemia, lipid profile, blood pressure, and body weight is essential for preventing chronic complications in type 2 diabetes,” Leite said. “Yet only a small portion of individuals with T2D achieve the recommended therapeutic targets,” she noted.

Numerous studies have shown that intensive interventions to meet all combined targets significantly reduce cardiovascular events and mortality, Leite noted.

While GLP-1 medications show benefits in each of these measures, the superiority of tirzepatide, a dual GLP-1/ glucose-dependent insulinotropic polypeptide agonist has not been demonstrated in the context of the goal of simultaneously achieving the control of all therapeutic targets.

SURPASS-2 Post Hoc Analysis

Leite and colleagues conducted the post hoc analysis of the multicenter, randomized, parallel-group SURPASS-2 trial, involving 1879 patients with T2D that was inadequately controlled with a metformin dose of at least 1500 mg/d.

In the study, patients were randomized to either tirzepatide 5 mg, 10 mg, or 15 mg vs semaglutide 1 mg. 

The mean age was 56.6 years, 53% were women, mean A1c was 8.3%, and mean BMI was 34.2. Patients had a median diabetes duration of 7.1 years.

For the primary endpoint of the trial, the change in A1c from baseline to 40 weeks was -2.01, -2.24, and -2.30 percentage points with tirzepatide doses of 5 mg, 10 mg, and 15 mg, respectively, vs -1.86 percentage points with semaglutide, indicating that “tirzepatide at all doses was noninferior and superior to semaglutide,” the SURPASS-2 authors reported.

For the current analysis, the assessed outcomes were the attainment of standard and intensive therapeutic targets, based on the American Diabetes Association’s Standards of Care in Diabetes.

Specifically, standard targets include A1c < 7.0%, blood pressure < 140/90 mm Hg, low-density lipoprotein (LDL) cholesterol < 70 mg/dL, and > 10% weight loss. 

The intensive targets are A1c < 6.5%, blood pressure < 130/80 mm Hg, LDL cholesterol < 55 mg/dL, and > 15% weight loss.

At baseline, the mean number of therapeutic targets achieved was 1.1 for standard targets and 0.5 for intensive targets, underscoring the uphill battle patients often face.

Factors associated with having attained more of the goals at baseline included being White, having lower mean A1c and fasting glucose, having lower waist circumference, and having lower blood pressure levels.

By the end of the study, those treated with tirzepatide at all doses achieved more of the standard goals than those treated with semaglutide (2.3, 2.5, and 2.6 with tirzepatide 5, 10, and 15 mg, respectively, vs 2.2 with semaglutide; P < .001).

Likewise, the rates of achieving the intensive goals were higher with tirzepatide (1.5, 1.7, and 1.9 with tirzepatide 5, 10, and 15 mg, respectively, vs 1.3 with semaglutide; P < .001). 

Of note, patients on tirzepatide did not have significant differences compared with those on semaglutide in terms of the achievement of blood pressure < 140/90 mm Hg (P = .13) or LDL cholesterol < 70 mg/dL (P = .94).

However, the rates of patients achieving three or more standard therapeutic targets were 42%, 53%, and 57% for those treated with tirzepatide at 5, 10, and 15 mg, respectively, vs 35% of those treated with semaglutide (odds ratio [OR] for pooled tirzepatide vs semaglutide, 1.91; P < .001). 

And for intensive targets, the corresponding rates for meeting three or more targets were 15%, 20%, and 29% for participants treated with tirzepatide at the 3 doses vs 8% for participants treated with semaglutide (OR, 3.09; P < .001).

“The most pronounced advantages of tirzepatide over semaglutide in this analysis were observed in glycemic control and weight management,” Leite said.

“Modest effects on LDL cholesterol were found with both tirzepatide and semaglutide.”

Commenting on the study, Shylaja Srinivasan, MD, an associate professor of pediatrics and director of the Pediatric Type 2 Diabetes Clinic at the University of California San Francisco, said the findings are consistent with the bulk of research showing improvements with tirzepatide compared with GLP-1s.

“It is not surprising to see the findings as tirzepatide does appear to be more efficacious than semaglutide,” Srinivasan said.

“A key caveat was that the comparisons were with 1 mg of semaglutide, which is not the highest dose available,” she noted. “A better comparison would be with the highest dose of semaglutide (2.4 mg) but that data is not available.”

Nevertheless, the study’s assessment of the simultaneous goals is a strength, Srinivasan said.

“This particular study looked at overall therapeutic targets, both standard and intensive, which was interesting to see compared to the usual A1c and weight only results.” 

The SURPASS-2 trial was funded by Eli Lilly. Leite reported having received consulting fees from BIAL. Srinivasan had no disclosures to report.