Cardiometabolic outcomes of once-weekly IcoSema in adults with type 2 diabetes: systematic review and meta-analysis of the COMBINE trials
- Design
- Meta-analysis · 1970 participants · Intermediate outcome
- Match to healthy normal-weight adults aged 55–75
- Different population[Auto] Synthesis of studies conducted predominantly in people with type 2 diabetes.
- Could weight loss explain it?
- Possibly[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.
- Study tier
- Study tier 2[Auto] Systematic review/meta-analysis of randomized trials (auto-provisional; heterogeneity and included-study quality not assessed).
- Assessment
- Version 1 · automatic, not yet reviewed by a person · Sep 13, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
[Auto, unreviewed; quoted from abstract conclusions] Once-weekly IcoSema delivers meaningful improvements in weight, blood pressure, and atherogenic lipids, all key modifiable drivers of ASCVD in adults with type 2 diabetes. These surrogate benefits, combined with reduced injection burden and low risk of hypoglycemia, suggest potential for enhanced ASCVD prevention and improved long-term adherence. Results should be interpreted as hypothesis-generating only because only two trials met the inclusion criteria. Dedicated cardiovascular outcome trials are essential to validate these surrogate-marker benefits and to confirm whether they translate into a reduction in cardiovascular events.
01Findings
What the study reported
- Drugs
- Semaglutide
- Primary outcome
- Not extracted
- Effect
- Not extracted
- 95% confidence interval
- Not extracted
- Follow-up
- Not stated
- Adverse events
- Not extracted
- Limitations
- Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.
Who was studied
- Diabetes status
- type 2 diabetes present (all or most)
- Cvd status
- cardiovascular disease present in population (see abstract)
- Sample size
- 1970
Study quality details
- Study design
- Meta-analysis
- Sample size
- 1970
- Randomization
- n/a
- Blinding
- not stated
- Comparator
- not stated
- Follow up duration
- not stated
- Outcome type
- intermediate
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: 95% CI -0
- Risk of bias
- not assessed (auto)
- Funding conflicts
- unclear
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- None identified
- Sponsor role
- not reported in abstract
- Author conflicts
- Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[BACKGROUND] Patients with type 2 diabetes face a high residual risk of atherosclerotic cardiovascular disease (ASCVD) despite advances in therapy. Once-weekly IcoSema, a fixed-ratio combination of basal insulin icodec and semaglutide, offers the potential to simultaneously address glycemic control, weight, and multiple cardiometabolic risk factors with a single weekly injection. [METHODS] We conducted a PRISMA-compliant systematic review and random-effects meta-analysis of randomized trials from the COMBINE program. Data from COMBINE 1 (active comparator: once-weekly insulin icodec) and COMBINE 3 (active comparator: basal-bolus insulin therapy) (N = 1,970) were pooled comparing IcoSema with insulin-based intensification strategies in patients inadequately controlled on basal insulin. COMBINE 2 was excluded because its semaglutide monotherapy comparator addresses a fundamentally different clinical question (escalation from GLP-1 RA monotherapy). The primary focus was on changes in body weight, Systolic blood pressure and HbA1c; key secondary outcomes included changes in lipid profile relevant to ASCVD risk. Certainty of evidence was assessed using GRADE. [RESULTS] IcoSema showed no statistically significant difference in HbA1c reduction compared with control (pooled MD -0.37%, 95% CI -0.95 to 0.21; P = 0.21; I²=98%) but shows highly significant body weight reduction (pooled MD -6.10 kg, 95% CI -7.21 to -5.00; P < 0.00001). It significantly lowered systolic blood pressure (MD -2.45 mmHg, 95% CI -3.52 to -1.38; P < 0.00001), total cholesterol (ETR 0.97, 95% CI 0.95-0.98; P = 0.0001), LDL-C (ETR 0.94, 95% CI 0.90-0.98; P = 0.005), triglycerides (ETR 0.94, 95% CI 0.91-0.97; P = 0.0006), and VLDL-C (ETR 0.94). An exploratory, hypothetical ASCVD risk modeling analysis based on these surrogate-marker changes is presented in the Supplementary Appendix and is intended as an illustration only. [CONCLUSIONS] Once-weekly IcoSema delivers meaningful improvements in weight, blood pressure, and atherogenic lipids, all key modifiable drivers of ASCVD in adults with type 2 diabetes. These surrogate benefits, combined with reduced injection burden and low risk of hypoglycemia, suggest potential for enhanced ASCVD prevention and improved long-term adherence. Results should be interpreted as hypothesis-generating only because only two trials met the inclusion criteria. Dedicated cardiovascular outcome trials are essential to validate these surrogate-marker benefits and to confirm whether they translate into a reduction in cardiovascular events.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Sep 13, 2026 | 42681675 first ingestion |