Dual Glucagon and GLP-1 Receptor Agonist Survodutide Improves Biomarkers of Beta-Cell Function and Insulin Sensitivity in People With Type 2 Diabetes or Living With Overweight/Obesity

Survodutide, a dual glucagon and GLP-1 receptor agonist, improved measures of beta-cell function and insulin sensitivity in two phase 2 trials, in people with type 2 diabetes on metformin and in people with overweight/obesity and normal glucose. It also lowered fasting glucose, glucagon, and insulin-related biomarkers compared with placebo, and these changes were largely not explained by weight loss.

Randomized controlled trial — post hoc analysis of two phase 2 RCTs. Population: Adults with type 2 diabetes on metformin; adults with overweight/obesity and normoglycaemia. Sample size: 413 participants with type 2 diabetes; 387 participants with overweight/obesity. Follow-up: 16 weeks (T2D trial); 46 weeks (overweight/obesity trial). Interventions: survodutide.

In trial 1404-0002 (413 participants with type 2 diabetes on metformin), survodutide significantly increased HOMA-β and decreased HOMA-IR, glucagon, and fasting plasma glucose versus placebo; HMW adiponectin, C-peptide, and fasting insulin did not change significantly. In trial 1404-0036 (387 participants with overweight/obesity and normoglycaemia), survodutide significantly decreased HOMA-IR, glucagon, C-peptide, fasting insulin, and FPG and increased HMW adiponectin versus placebo, with no significant change in HOMA-β. Bodyweight change explained the largest proportion of variability in changes in fasting insulin and HOMA-IR across dose groups but did not explain other biomarker changes.

For researchers studying survodutide or semaglutide, this paper provides biomarker-level evidence that dual glucagon/GLP-1 agonism may improve beta-cell function and insulin sensitivity beyond weight loss. It does not establish long-term durability, clinical outcomes, or causality, and dose-specific effect sizes were not reported in the abstract.

Key findings

In a 16-week trial of 413 adults with type 2 diabetes on metformin, survodutide significantly increased HOMA-β and decreased HOMA-IR, glucagon, and fasting plasma glucose versus placebo.
In a 46-week trial of 387 adults with overweight/obesity and normoglycaemia, survodutide significantly decreased HOMA-IR, glucagon, C-peptide, fasting insulin, and FPG and increased HMW adiponectin versus placebo.
No significant change in HOMA-β was seen with survodutide in the normoglycaemic overweight/obesity trial.
Across both trials, bodyweight change explained the largest proportion of variability in changes in fasting insulin and HOMA-IR, but not in other biomarker changes.

Limitations

Authors note that the durability of beta-cell improvements after treatment cessation remains unknown.
This was a post hoc analysis, so the findings are exploratory and were not prespecified.
The two trials had different populations, durations, and comparator sets, limiting direct comparability.
Weight-change analyses were descriptive and regression-based and cannot prove independence from weight loss.

The record

Journal: Diabetes, obesity & metabolism 28(9): 8242-8253
Published: 2026-06-22
PMID: 42331726 — DOI: 10.1111/dom.70861
MeSH terms: Humans, Diabetes Mellitus, Type 2, Insulin Resistance, Obesity, Metformin, Glucagon, Blood Glucose, Peptide Fragments, Hypoglycemic Agents, Drug Therapy, Combination, Double-Blind Method, Adult, Aged, Middle Aged, Female, Male, Overweight, Insulin-Secreting Cells, Glucagon-Like Peptides, Biomarkers, Glucagon-Like Peptide-1 Receptor Agonists, Diabesity, Semaglutide
Funding: Boehringer Ingelheim
Author countries: Australia, Germany

Peptide profiles: Survodutide, Semaglutide.

All indexed evidence: Survodutide trials & papers, Semaglutide trials & papers.