What is the clinical evidence from this study?

Study design: RCT. Population: Obesity and prediabetes (n=425). Intervention: Tirzepatide vs. Semaglutide 1.7 mg or 2.4 mg once weekly. Primary outcome: Reversion to normoglycemia (HbA1c < 5.7% and FSG < 100 mg/dL) at Week 72 (Risk difference 11.4%, 95% CI 4.2, 18.6, p=0.002).

What question did this study set out to answer?

This analysis aims to compare the effects of tirzepatide and semaglutide on glycemia outcomes in individuals with obesity and prediabetes.

April 22, 2026Open Access

Reversion to normoglycemia with tirzepatide vs semaglutide in participants with obesity and prediabetes: a post hoc analysis of SURMOUNT-5

Q: What are the key findings of this study?

Tirzepatide resulted in a significantly greater proportion of participants with obesity and prediabetes reverting to normoglycemia compared with semaglutide (89.9% vs 76.2%) at 72 weeks.

Q: What does this research mean for the field?

Tirzepatide results in a significantly greater proportion of participants with obesity and prediabetes reverting to normoglycemia compared with semaglutide at 72 weeks. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

This analysis aims to compare the effects of tirzepatide and semaglutide on glycemia outcomes in individuals with obesity and prediabetes.

Key Result

Tirzepatide resulted in a significantly greater proportion of participants with obesity and prediabetes reverting to normoglycemia compared with semaglutide (89.9% vs 76.2%) at 72 weeks.

Key Points

This analysis aims to compare the effects of tirzepatide and semaglutide on glycemia outcomes in individuals with obesity and prediabetes.
Analyzed data from the SURMOUNT-5 trial with 425 participants having prediabetes.
Compared changes in HbA1c and body weight after 72 weeks of treatment using logistic regression and MMRM.
Included fasting insulin and insulin sensitivity estimates in assessments.
Mean HbA1c reduction was greater with tirzepatide (-0.60%) compared to semaglutide (-0.48%; p < 0.001).
89.9% of participants using tirzepatide achieved normoglycemia, versus 76.2% with semaglutide.
Body weight reduction was significantly higher with tirzepatide (-21.5% vs -14.5%; p < 0.001).

Study Design

Type

RCT (n=425)

Blinding

Open-label

Randomization

1:1

Multicenter

Yes

Structured PICO

Does tirzepatide improve glycemic control and body weight compared to semaglutide in adults with obesity and prediabetes?

Population

425 adults (aged ≥ 18 years) with obesity (BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with at least one obesity-related complication) and prediabetes (defined as ≥ 1 fasting lab-based value of FSG 100–125 mg/dL or HbA1c 5.7–6.4%), mean age 47.3 years, 63% female.

Intervention

Tirzepatide once weekly at maximum tolerated dose (10 mg or 15 mg) as an adjunct to a reduced calorie diet and increased physical activity for 72 weeks.

Comparator

Semaglutide once weekly at maximum tolerated dose (1.7 mg or 2.4 mg) as an adjunct to a reduced calorie diet and increased physical activity for 72 weeks.

Outcome

Change from baseline in HbA1c at Week 72.surrogate

In adults with obesity and prediabetes, tirzepatide provided superior improvements in glycemic control, reversion to normoglycemia, and body weight reduction compared to semaglutide.

Main Result

Effect estimate: Risk difference 11.4% (95% CI 4.2, 18.6)

Absolute Event Rate: 89.9% vs 76.2%

p-value: p=0.002

Limitations

Post hoc analysis and exploratory in nature
Open-label design may have introduced potential differences in adherence and behavioral co-interventions
Static model-based estimates of insulin resistance were used, and beta-cell function was not dynamically assessed
70% of participants were White, which may limit generalizability

Abstract

Prevention of progression into type 2 diabetes (T2D) in patients with prediabetes is a key goal of obesity management. In SURMOUNT-5, once weekly tirzepatide at the maximum tolerated dose (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) resulted in significantly greater body weight reduction in adults living with obesity without T2D. Assess changes in glycemia outcomes with tirzepatide (MTD 10 mg or 15 mg) compared with semaglutide (MTD 1.7 mg or 2.4 mg) in participants with obesity and prediabetes from SURMOUNT-5. Participants (N = 425) with baseline prediabetes, defined as having ≥ 1 fasting lab-based value of either FSG 100–125 mg/dL or HbA1c 5.7–6.4%, were included in this analysis. Change from baseline in HbA1c, proportion of participants achieving normoglycemia (i.e., HbA1c < 5.7% and FSG < 100 mg/dL), percent change from baseline in body weight, fasting insulin, estimates of insulin sensitivity (HOMA2-IR), and proportion of participants achieving body weight reduction thresholds (≥ 10% to ≥ 30%) at Week 72 were assessed using MMRM or logistic regression for categorical measures using the efficacy analysis set. Mean baseline age was 47 years, 63% were female, BMI was 40 kg/m2, and HbA1c was 5.86%. At Week 72, mean HbA1c reduction was significantly greater with tirzepatide vs semaglutide (-0.60% vs -0.48%; estimated treatment difference ETD; 95% CI -0.12% −0.18, −0.06; p < 0.001). A greater proportion of tirzepatide-treated participants reverted to normoglycemia (89.9%) vs semaglutide (76.2%). Mean percent body weight reduction was significantly greater with tirzepatide (−21.5% vs -14.5%; ETD −7.1% −9.1, −5.0; p < 0.001). Greater improvements in fasting insulin and HOMA2-IR were observed with tirzepatide vs semaglutide (p < 0.001). In this post hoc analysis of SURMOUNT-5, a greater proportion of tirzepatide-treated participants with obesity and prediabetes at baseline reverted to normoglycemia compared with semaglutide. Greater improvements in glycemia, estimates of insulin sensitivity and body weight were also observed with tirzepatide.

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