suPAR Identifies Treatment-Resistant Inflammatory Risk Beyond hs-CRP in Type 2 Diabetes With Coronary Artery Disease: An Ancillary Analysis of BARI 2D

Q: What are the key findings of this study?

Baseline suPAR independently predicted the composite outcome of death, myocardial infarction, or stroke (adjusted HR 1.40 per SD) and was unmodified by randomized diabetes or revascularization strategies over 1 year.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Type 2 diabetes and coronary artery disease (n=2277). Intervention: Elevated baseline suPAR vs. Lower baseline suPAR. Primary outcome: Composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke (HR 1.40, 95% CI 1.27-1.55, p=<0.001).

Q: What does this research mean for the field?

In patients with type 2 diabetes and coronary artery disease, elevated suPAR independently predicts all-cause mortality, myocardial infarction, and stroke, persisting despite intensive medical and revascularization treatments and identifying residual inflammatory risk even after hs-CRP normalization. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

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

To determine whether plasma suPAR levels are altered by randomized diabetes or revascularization strategies in patients with type 2 diabetes and coronary artery disease, and whether suPAR refines residual cardiovascular risk stratification beyond hs-CRP.

Anis Ismail; Yiyuan Huang; Bahjat Ghazzal; Christina Hutten; Theresa Farhat; Ramya Elangovan; Bobby Bobby; Pennelope Kunkle; Alexi Vasbinder; Mousumi Banerjee; Arshed Quyyumi; Richard E. Pratley; Maria M. Brooks; Rodica Pop‐Busui; Salim S. Hayek

doi:10.2337/dc26-0899

August 11, 2026Diabetes CareOpen Access

suPAR Identifies Treatment-Resistant Inflammatory Risk Beyond hs-CRP in Type 2 Diabetes With Coronary Artery Disease: An Ancillary Analysis of BARI 2D

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Key result

Higher baseline suPAR linked to ~40% greater risk of death, MI, or stroke per SD.

HR 1.40
95% CI 1.27-1.55
P<0.001
n=2,277

Diabetes Care published a graphical abstract

Its licence doesn't allow us to show a copy here.

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Why the study?

It was unknown whether suPAR is modified by randomized diabetes and revascularization strategies in type 2 diabetes and coronary artery disease, and whether combining suPAR and hs-CRP refines residual risk stratification.

Does prompt revascularization or insulin-sensitization therapy modify suPAR levels, and does suPAR predict cardiovascular events in patients with type 2 diabetes and coronary artery disease?

Key Points

To determine whether plasma suPAR levels are altered by randomized diabetes or revascularization strategies in patients with type 2 diabetes and coronary artery disease, and whether suPAR refines residual cardiovascular risk stratification beyond hs-CRP.
Conducted an ancillary analysis of the randomized BARI 2D trial measuring plasma suPAR and hs-CRP at baseline (n = 2,277) and 1 year (landmark cohort, n = 1,978).
Participants were randomized 2×2 to glycemic control strategies (insulin sensitization vs. insulin provision) and cardiac strategies (prompt revascularization vs. medical therapy), with a median follow-up of 5.0 years.
Used sequentially adjusted Cox proportional hazards models to assess associations with the primary composite outcome of all-cause death, nonfatal myocardial infarction, or nonfatal stroke.
Over 1 year, suPAR was not lowered by diabetes or cardiac strategies (median 2.96 to 3.15 ng/mL; all-treatment arm P ≥ 0.75), whereas hs-CRP declined substantially (median 2.07 to 1.30 mg/L).
The primary composite outcome occurred in 526 participants (23.1%), with baseline suPAR independently predicting risk (adjusted HR 1.40 per SD, 95% CI 1.27–1.55) across tertiles (12.9%, 23.1%, and 33.3%; P < 0.001 for trend).
Baseline suPAR predicted events even among participants whose hs-CRP normalized (HR 1.45, 95% CI 1.04–2.03) and modified glycemic treatment response (P-interaction = 0.005), with insulin provision yielding worse outcomes in the highest suPAR tertile (HR 1.33, 95% CI 1.03–1.72).

Study Design

Type

Cohort (n=2,277)

Blinding

Laboratory personnel blinded to treatment assignment and clinical outcomes

Randomization

Randomized 2x2 factorial for parent trial

Multicenter

Yes

Structured PICO

Does prompt revascularization or insulin-sensitization therapy modify suPAR levels, and does suPAR predict cardiovascular events in patients with type 2 diabetes and coronary artery disease?

P

Population

2,277 adults (mean age 62, 29.8% female) with type 2 diabetes and coronary artery disease from the BARI 2D trial, followed for a median of 5.0 years to assess the prognostic value of suPAR.

E

Exposure

Prompt coronary revascularization (PCI or CABG) and/or insulin-sensitization therapy (metformin, rosiglitazone, or both) to achieve HbA1c <7.0%

C

Comparator

Intensive medical therapy alone and/or insulin-provision therapy (insulin or sulfonylureas) to achieve HbA1c <7.0%

O

Outcome

First occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal strokecomposite

Main Result

Hazard Ratio: 1.4 (95% CI 1.27–1.55)

p-value: p=<0.001

suPAR identifies a treatment-resistant inflammatory risk pathway in type 2 diabetes with coronary artery disease that is not modified by standard revascularization or diabetes therapies and persists even when hs-CRP normalizes.

Limitations

Preceded widespread use of GLP-1 RAs, SGLT2 inhibitors, and newer lipid-lowering therapies
Reassessment limited to 1 year
Landmark cohort excluded 299 participants with missing 1-year measurements
Cannot test whether interventions lowering suPAR reduce cardiovascular events
suPAR by diabetes strategy interaction was not prespecified

Key expert perspectives

Captured external expert commentary on this paper, strongest first. Original sources are linked where available.

SH Salim HayekCardiologist, chair of internal medicine, UTMB

“Inflammation is not a single process. It is a complex network of biological pathways, and hs-CRP captures only part of that picture. Our findings show that suPAR reflects a different part of the immune system, one that conventional therapies do not appear to reach and that hs-CRP does not capture.”

University of Texas Medical BranchNews Coverage

Implication

suPAR marks persistent cardiovascular risk unmodified by revascularization or diabetes therapy; leaves open whether pathway-specific interventions improve outcomes.

Abstract

OBJECTIVE To determine whether soluble urokinase plasminogen activator receptor (suPAR) is modified by randomized diabetes and revascularization strategies in patients with type 2 diabetes and coronary artery disease and whether combined suPAR and hs-CRP classification refines residual cardiovascular risk stratification. RESEARCH DESIGN AND METHODS In this ancillary analysis of Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D), we measured plasma suPAR and hs-CRP at baseline (n = 2,277) and 1 year (landmark cohort, n = 1,978). The primary outcome was all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Associations were assessed using sequentially adjusted Cox models. RESULTS Over 1 year, suPAR was not reduced by diabetes (insulin sensitizing vs. insulin provision) or cardiac (revascularization vs. medical therapy) treatment strategies (median 2.96–3.15 ng/mL; all-treatment arm P ≥ 0.75), while hs-CRP declined substantially (median 2.07–1.30 mg/L). suPAR independently predicted the composite outcome (adjusted hazard ratio [HR] 1.40 per SD; 95% CI 1.27–1.55), unattenuated after hs-CRP adjustment. In an exploratory analysis, suPAR modified the diabetes treatment effect (P-interaction = 0.005), with insulin provision associated with worse outcomes in the highest suPAR tertile (HR 1.33; 95% CI 1.03–1.72). Baseline suPAR predicted risk in participants whose hs-CRP normalized (HR 1.45; 95% CI 1.04–2.03). Joint classification revealed a threefold gradient in event rates (7.1% to 21.6%), with elevated suPAR conferring excess risk even after hs-CRP normalization. CONCLUSIONS Over 1 year, suPAR was unmodified by diabetes or revascularization strategies in BARI 2D despite intensive guideline-directed medical optimization, in contrast to hs-CRP, which declined substantially. Combined suPAR and hs-CRP classification produced a graded risk hierarchy that hs-CRP normalization alone did not resolve.

Discussion

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Cite This Study

Ismail et al. (2026) conducted a cohort in Type 2 diabetes and coronary artery disease (n=2,277). Elevated baseline suPAR vs. Lower baseline suPAR was evaluated on Composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke (HR 1.40, 95% CI 1.27-1.55, p=<0.001). Baseline suPAR independently predicted the composite outcome of death, myocardial infarction, or stroke (adjusted HR 1.40 per SD) and was unmodified by randomized diabetes or revascularization strategies over 1 year.

synapsesocial.com/papers/6a7d76412b0e0cff3f63f67b https://doi.org/10.2337/dc26-0899

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suPAR Identifies Treatment-Resistant Inflammatory Risk Beyond hs-CRP in Type 2 Diabetes With Coronary Artery Disease: An Ancillary Analysis of BARI 2D

Diabetes Care published a graphical abstract

Key Points

Study Design

Structured PICO

Main Result

Limitations

Key expert perspectives

Implication

Abstract

Discussion

Cite This Study

suPAR Identifies Treatment-Resistant Inflammatory Risk Beyond hs-CRP in Type 2 Diabetes With Coronary Artery Disease: An Ancillary Analysis of BARI 2D

Diabetes Care published a graphical abstract

Key Points

Study Design

Structured PICO

Main Result

Limitations

Key expert perspectives

Implication

Abstract

Discussion

Cite This Study

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