Relation of Serum and Urine Renal Biomarkers to Cardiovascular Risk in Patients with Type 2 Diabetes Mellitus and Recent Acute Coronary Syndromes (From the EXAMINE Trial)

https://doi.org/10.1016/j.amjcard.2018.10.035Get rights and content

A deeper understanding of the interplay between the renal axis and cardiovascular (CV) disease is needed in type 2 diabetes mellitus (T2DM). We aimed to explore the prognostic value of a comprehensive panel of renal biomarkers in patients with T2DM at high CV risk. We evaluated the prognostic performance of both serum (Cystatin C) and urine renal biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 protein, and indices of urinary protein excretion) in 5,380 patients with T2DM and recent acute coronary syndromes in the EXAMINE trial. Patients requiring dialysis within 14 days were excluded. Single- and multimarker covariate-adjusted Cox proportional hazards models were developed to predict times to events. Primary endpoint was composite nonfatal myocardial infarction, nonfatal stroke, or CV death. Median age was 61 years, 68% were men, and mean baseline estimated glomerular filtration rate (eGFR) was 74 mL/min/1.73 m2. During median follow-up of 18 months, 621 (11.5%) experienced the primary endpoint and 326 (6.1%) patients had died. All renal biomarkers were robustly associated with adverse CV events in step-wise fashion, independent of baseline eGFR. However, in the multimarker prediction model, only Cystatin C (per 1 SD) was associated with the primary endpoint (hazard ratio [HR] 1.28 [1.14 to 1.45]; p ≤ 0.001), death (HR 1.51 [1.30 to 1.74]; p ≤ 0.001), and heart failure hospitalization (HR 1.20 [0.96 to 1.49]; p = 0.11). Association between Cystatin C and the primary endpoint was similar in baseline eGFR above and below 60 mL/min/1.73 m2 (Pinteraction > 0.05). In conclusion, serum and urine renal biomarkers, when tested alone, independently predict long-term adverse CV events in high-risk patients with T2DM. In an integrative panel of renal biomarkers, only serum Cystatin C remained independently associated with subsequent CV risk. Renal biomarkers informing various aspects of kidney function may further our understanding of the complex interplay between diabetic kidney disease and CV disease.

Section snippets

Methods

The design11 and primary results12 of EXAMINE have been previously published. In brief, EXAMINE was a global, multicenter, trial of adult patients with T2DM (glycated hemoglobin levels 6.5% to 11.0%) and recent ACS (within 15 to 90 days before randomization) who were randomly assigned to alogliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, or matching placebo in 1:1 double-blinded fashion. Both treatment arms received standard of care for T2DM and secondary CV protection. Patients deemed

Results

Of the 5,380 patients enrolled in EXAMINE, all patients had a calculated CKD-EPI eGFR, 5,213 (97%) had serum Cystatin C values, 4,875 (91%) had uKIM-1/Cr, 4,962 (92%) had uNGAL/Cr, 4,049 (75%) had urine protein/Cr ratio, and 3,135 (58%) had an albumin/Cr ratio measured at randomization (median 44 days from qualifying ACS) and available for analysis.

EXAMINE enrolled older adults (mean age, 61 years) who were predominantly men (68%) and White (73%). Patients commonly had co-morbid hypertension

Discussion

In a large, well-characterized cohort of patients with T2DM, 4 urinary biomarkers and 1 serum renal biomarker measured early after index ACS were robustly associated with risk of subsequent CV events and death in step-wise manner, independent of baseline eGFR. The highest quartiles of these renal biomarkers informing various axes of renal function identified patients who face the highest risks of major adverse CV events (18% to 25% at 2 years). However, when tested together, only serum Cystatin

Disclosures

Muthiah Vaduganathan: Research support from the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst | The Harvard Clinical and Translational Science Center (NIH/NCATS Award UL 1TR002541), and serves on advisory boards for AstraZeneca, Bayer AG, and Baxter Healthcare.

William B. White: Research support from National Institutes of Aging (RO1 AG 0220902) and Chair of the EXAMINE steering committee with personal fees from Takeda Development Center from 2010 to 2016.

David

Acknowledgments

EXAMINE was supported by Takeda Development Center, North America, Deerfield, IL, USA. We would like to thank the 898 site investigators and the patients of EXAMINE for their participation in the trial.

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    Source of Support: The EXAMINE trial was supported by Takeda Development Center Americas.

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