Research Library

TZ vs SM: The 2025 obesity head-to-head trial Head-to-Head

This is the only major incretin comparison supported by direct head-to-head trials. SM, however, has the longer cardiovascular outcome record.

Summary

This is the only major incretin comparison supported by direct head-to-head trials. SM, however, has the longer cardiovascular outcome record.

Last reviewed 2026-09-01

What it is

A comparison of SM, a GLP-1 receptor agonist, with TZ, a GIP/GLP-1 dual receptor agonist, based on trials that randomised participants to both.

SM reached obesity indications through the STEP programme from 2021; TZ followed through its phase 3 obesity programme. The 2021 diabetes head-to-head trial (2021) and 2025 obesity head-to-head trial (2025) provided the direct comparisons.

Both are synthetic, long-acting incretin analogues designed for weekly administration.

It is the rare case in this field where a comparison rests on randomised head-to-head data rather than cross-trial arithmetic.

How it works

In plain terms

SM acts on one gut hormone receptor; TZ acts on two.

Technical detail

SM is a GLP-1 receptor agonist with albumin-binding fatty acid modification giving a roughly one-week half-life. TZ additionally activates the GIP receptor, with higher affinity for GIPR than GLP-1R. The contribution of GIP receptor activity is mechanistically contested: both agonism and antagonism of GIPR have shown weight benefit in different models, and adipose GIPR signalling plus central effects are proposed explanations. Both slow gastric emptying, enhance glucose-dependent insulin secretion and reduce appetite centrally.

Pathways involved

GLP-1R agonism: satiety, gastric emptying, insulinotropic effect
GIPR agonism (TZ): adipose and central contributions
Albumin-binding acylation for weekly dosing

Current research

Laboratory research

Receptor binding and signalling bias profiles are published for both.

Animal research

Outcome details are reported in the cited peer-reviewed literature.

Human research

Outcome details are reported in the cited peer-reviewed literature.

Ongoing research

TZ cardiovascular and outcome trials continue to report.

What is being investigated

Relative weight and glycaemic efficacy
The mechanistic contribution of GIP receptor activity
Tolerability and discontinuation rates at comparable doses
Cardiovascular and organ-specific outcomes beyond weight

These are research directions reported in the literature, not established effects or recommendations.

Risks, limitations and unknowns

Read this section before the rest

Outcome details are reported in the cited peer-reviewed literature.
Gastrointestinal adverse events were common with both in head-to-head trials
The 2021 diabetes head-to-head trial used SM 1 mg, a diabetes dose lower than the 2.4 mg obesity dose
Outcome details are reported in the cited peer-reviewed literature.
Outcome details are reported in the cited peer-reviewed literature.

Evidence ratings

Head-to-head human data

Strong

The 2021 diabetes head-to-head trial and 2025 obesity head-to-head trial randomised direct comparisons.

SM outcome data

Strong

SELECT cardiovascular outcome trial.

TZ outcome data

Moderate

Outcome programmes still maturing.

GIPR mechanism

Limited

Contribution of GIPR agonism remains contested.

Comparisons

RT vs tz

No head-to-head data exists there.

Cagrilintide vs SM

Amylin versus incretin mechanism.

References

[1]The 2021 diabetes head-to-head trial head-to-head trial — PubMed / NEJM, 2021
[2]The 2025 obesity head-to-head trial head-to-head obesity trial — PubMed / NEJM, 2025
[3]SELECT cardiovascular outcomes trial — PubMed / NEJM, 2023
Reference links open searches and records on PubMed and ClinicalTrials.gov so that every statement above can be traced to primary literature.

Frequently asked questions

Is TZ therefore better?+

Not straightforwardly. SM has stronger cardiovascular outcome evidence from SELECT, and outcomes matter beyond weight.

What is 2025 obesity head-to-head trial?+

A randomised head-to-head obesity trial comparing TZ with SM 2.4 mg over 72 weeks.

Why did 2021 diabetes head-to-head trial use SM 1 mg?+

It was a type 2 diabetes trial, and 1 mg was the approved diabetes dose at the time — lower than the obesity dose.

Does GIP receptor activation explain the difference?+

Probably in part, but the mechanism is contested: both GIPR agonism and antagonism have shown weight benefit in different models.

Are side effects different?+

Both cause dose-related gastrointestinal effects; head-to-head trials did not show a large tolerability separation.

Continue your research

SM research

TZ research

Incretin side effects