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Focus on...

9 March 2015
Do emerging risk factors contribute to residual cardiovascular risk?
Beyond traditional lipid risk factors, a new analysis from the Treating to New Targets (TNT) study shows that several emerging risk factors, including lipoprotein(a), contribute to cardiovascular risk.
Arsenault BJ, Barter P, DeMicco DA et al; Treating to New Targets (TNT) Investigators. Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers. PLoS One 2014;9(12):e114519.
Objective: To investigate the ability of a number of lipid and non-lipid biomarkers to predict major cardiovascular events (MCVEs) in stable, statin-treated coronary heart disease (CHD) patients.
Study design: Substudy of the TNT study, a randomized, double-blind prospective study comparing 10 mg and 80 mg atorvastatin in CHD patients with low-density lipoprotein cholesterol (LDL-C) levels <3.4 mmol/L (<130 mg/dL). Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1,349 controls.  
Study population: 10,001 patients with LDL-C levels <3.4 mmol/L (<130 mg/dL) were randomized in the main TNT study; data from 1506 patients (mean age 61.5 years, 80% male, baseline LDL-C 98 mg/dL or 2.5 mmol/L) were included in this substudy.  
Primary variable: MCVE, defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke.

Biomarkers were selected on the basis of having previously shown potential utility in improving cardiovascular disease risk prediction in human clinical and population studies. Biomarkers evaluated were:
·       high-sensitivity C-reactive protein (hsCRP; inflammatory marker)
·       monocyte chemotactic protein-1 (MCP-1); neopterin; soluble intercellular adhesion molecule-1 (sICAM-1); soluble vascular cell adhesion molecule-1 (sVCAM-1) (biomarkers of macrophage recruitment/activity)
·       myeloperoxidase (MPO); lipoprotein-associated phospholipase A2 (Lp-PLA2) (biomarkers of oxidative stress)
·       matrix metalloproteinase-9 (MMP-9); osteopontin (biomarkers of tissue remodelling)
·       soluble CD40 ligand (sCD40L); lipoprotein(a) [Lp(a)] (biomarkers of platelet/thrombosis activity)
·       insulin; adiponectin; high molecular weight (HMW) adiponectin; HMW/total adiponectin (ratio); soluble receptor for advanced glycation end-products (sRAGE) (biomarkers of insulin resistance)
·       N-terminal fragment of pro-B-type natriuretic peptide (NT-pro-BNP) (biomarker of congestive heart failure)
·       Cystatin C (biomarker of kidney function)

The association between on-treatment lipids and biomarker levels (at the time of randomization and at 1 year) and the primary endpoint was assessed in Cox proportional hazard analyses after adjustment for age, gender and treatment effect, using time to primary end point as the dependent variable for all patients and for patients within each treatment group.

Main results:

·       Plasma levels of hsCRP, insulin, neopterin, NT-proBNP, Lp(a), and sRAGE were predictive of recurrent MCVEs (p£0.02 for each doubling of plasma concentration).

·       After further adjustment for diabetes, hypertension, smoking, and body mass index, only the relationship between Lp(a), neopterin, NT-proBNP  and sRAGE and MCVEs remained statistically significant. The relationship between NT-proBNP and Lp(a) with cardiovascular risk was also observed 1 year following randomization (Table).

Table. Relationship between biomarkers at randomization and MCVEs


Hazard ratio (95% CI) at randomization

Hazard ratio (95% CI) at 1 year


1.13 (1.03, 1.25)*

1.17 (1.04, 1.33)*


1.56 (1.25, 1.94)****

1.18 (0.86, 1.63)


2.03 (1.53, 2.68)****


1.70 (1.20, 2.41)**


1.54 (1.20, 1.98)***

1.17 (0.86, 1.58)

* p<0.05; **p<0.01;***p<0.001; ****p<0.0001

  • Plasma levels of adiponectin, cystatin C, Lp-PLA2, MCP-1, MMP-9, MPO, osteopontin, sCD40L, sICAM-1, and sVCAM-1 were not associated with risk of recurrent MCVEs.
Authors’ conclusion: In conclusion, in patients with CHD treated with atorvastatin and with LDL-C levels at goal, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs.


Much of the focus in addressing residual cardiovascular risk has been on the lipid-related component of this risk. The Residual Risk Reduction Initiative, in agreement with other expert consensus groups, has made the case for consideration of atherogenic dyslipidaemia, the combination of elevated triglycerides and low plasma concentration of high-density lipoprotein cholesterol (HDL-C) as an important contributor to lipid-related residual cardiovascular risk.1,2. Indeed, evidence discussed in this month’s Landmark study highlights atherogenic dyslipidaemia as an important contributor in statin-treated patients with prior cerebrovascular disease.3 Furthermore, in the current analysis from the TNT study, HDL-C and triglycerides measured at randomization were predictive of major cardiovascular events.

However, other modifiable non-lipid factors may also contribute to residual cardiovascular risk. Given that atherosclerosis is a chronic inflammatory disease, there has been much debate regarding the potential contribution of inflammatory markers, such as C-reactive protein.4 Whether direct inhibition of inflammation will reduce the occurrence of cardiovascular events is the focus of ongoing trials, such as the Cardiovascular Inflammation Reduction Trial (CIRT) in patients with prior myocardial infarction (MI) and type 2 diabetes or metabolic syndrome.5 In the current analysis, however, multivariate analysis, adjusting for diabetes, hypertension, smoking and body mass index did not support a role for inflammatory markers such as CRP as contributors to cardiovascular risk in statin-treated patients.

Another biomarker attracting renewed attention as a cardiovascular risk factor is Lp(a). Recent evidence supports elevated Lp(a) as a causal risk factor for the development of atherosclerosis and cardiovascular disease, independent of LDL cholesterol levels.6 Additionally, Lp(a) has been implicated as a contributor to residual cardiovascular risk in a low-risk group characterised by low LDL-C levels, as in the JUPITER study.7 The current analysis is consistent with this body of support for Lp(a) as a contributor to residual cardiovascular risk. Interestingly, the strongest impact on cardiovascular risk was observed with NT-proBNP, for which a doubling of plasma concentration was associated with a doubling of cardiovascular risk. Findings from the Emerging Risk Factor Collaboration support the impact of NT-proBNP levels on cardiovascular disease risk.8

Taken together, the findings from this analysis of the TNT study highlight the relevance of considering non-lipid biomarkers as contributors to cardiovascular risk beyond conventional lipids in statin-treated patients, and suggest future potential for therapeutic targeting.  


1. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26

2. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.

3. Sirimarco G, Labreuche J, Bruckert E et al; on behalf of the PERFORM and SPARCL Investigators and Committees. Atherogenic dyslipidemia and residual cardiovascular risk in statin-treated patients. Stroke 2014;45:1429-36.

4. Chapman MJ, Giral P, Barter PJ. The conundrum of C-reactive protein as a risk marker for cardiovascular risk assessment: insight from EPIC-Norfolk and JUPITER.  Eur Heart J 2013;34:1318-20.

5. Everett BM, Pradhan AD, Solomon DH et al. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J 2013;166:199-207.

6. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.

7. Khera AV, Everett BM, Caulfield MP et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin).Circulation 2014;129:635-42.

8. Di Angelantonio E, Chowdhury R, Sarwar Net al. B-type natriuretic peptides and cardiovascular risk: systematic review and meta-analysis of 40 prospective studies. Circulation 2009;120: 2177–87.

Key words biomarker; lipoprotein(a); cardiovascular risk