NT–proBNP has additive predictive value for heart failure in diabetic patients

Cardiac Stress and Inflammatory Markers as Predictors of Heart Failure in Patients With Type 2 Diabetes: The ADVANCE Trial

Literature - Ohkuma T, Jun M, Woodward M, et al; ADVANCE Collaborative Group. - Diabetes Care. 2017; published online ahead of print


Diabetes increases the risk of heart failure (HF) by more than 50% and has a negative impact on HF prognosis [1,2]. Thus, the prevention and treatment of HF in diabetic patients as well as their HF risk stratification are important, however there are limited data regarding the use of cardiovascular disease-related biomarkers in this setting [3].

In this study, the association of the markers NT-proBNP, hs-cTnT, hs-CRP and IL-6 with risk of HF was evaluated in type 2 diabetes mellitus (T2DM) patients. Moreover, the additional risk-predictive ability of these markers was assessed, on top of traditional clinical risk factors. For this purpose, a nested case-cohort study was conducted including patients from the ADVANCE study, in which 11,140 T2DM patients at high cardiovascular risk were randomized to an intensive gliclazide modified release-based glucose control regimen or standard guidelines-based therapy and after a 6-week run-in period, to perindopril-indapamide or matching placebo [4-6]. In the end, 3,098 patients were included in the analysis. The study outcome was the incidence or progression of HF (death due to HF, HF hospitalization or worsening of NYHA classification).

Main results

  • During a median follow-up of 5 years, 237 patients who experienced an HF event had significantly higher levels of IL-6, hs-CRP, hs-cTnT and NT-proBNP.
  • HF risk increased significantly with increasing levels of all biomarkers after adjustment for age, gender, randomized blood pressure–lowering, glucose-control interventions and clinical risk factors (all P for trend <0.01).
  • The multivariable-adjusted HRs for HF according to the highest fifths compared with the lowest fifths of each biomarker were 2.62 for IL-6 (95% CI: 1.48–4.63), 2.22 for hs-CRP (95% CI: 1.33–3.72), 2.70 for hs-cTnT (95% CI: 1.68–4.34), 12.53 for NT-proBNP (95% CI: 5.41–29.02).
  • Higher values of all four biomarkers were significantly associated with a higher risk of HF after adjusting for clinical risk factors (all P<0.001).
  • After further adjustment for the other studied biomarkers, the associations were attenuated and became non-significant for hs-CRP and hs-cTnT.
  • NT-proBNP showed the strongest association with HF (HR 2.77, 95% CI 2.12–3.63).
  • Significant heterogeneity (P=0.004) was observed in the association of patients with (HR 2.28, 95% CI 1.08–4.81) and without (HR 3.52, 95% CI 2.66–4.66) a history of myocardial infarction.
  • The addition of NT-proBNP to a model including conventional risk factors greatly improved discrimination and classification of the 5-year HF risk (C statistic: 0.8162-0.8800; P<0.001, integrated discrimination index [IDI] 0.107, P<0.001, continuous net reclassification improvement [NRI] 0.731, P<0.001, categorical NRI 0.242, P<0.001).
  • The improvements were not uniformly significant when adding IL-6, hs-CRP or hs-cTnT to the above model.


In T2DM patients at high cardiovascular risk, markers IL-6, hs-CRP, hs-cTnT and NT-proBNP were independent predictors of the incidence of HF, but only the addition of NT-proBNP improved the predictive performance for HF on top of conventional clinical risk factors.


1. Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1-9 million people. Lancet Diabetes Endocrinol 2015;3:105–113

2. Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J 2006;27:65–75

3. McMurray JJ, Gerstein HC, Holman RR, et al. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol 2014;2:843–851

4. ADVANCE Management Committee. Study rationale and design of ADVANCE: action in diabetes and vascular disease–preterax and Diamicron MR controlled evaluation. Diabetologia 2001;44:1118–1120

5. Patel A, MacMahon S, Chalmers J, et al.; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular andmicrovascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; 370:829–840

6. Patel A, MacMahon S, Chalmers J, et al.; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2diabetes.NEngl JMed 2008;358:2560–2572

Find this article online at Diabetes care

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