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18 September 2016
New analysis supports targeting non-HDL cholesterol, triglycerides to reduce plaque progression

Achieved non- high density cholesterol (non-HDL-C) and triglyceride levels significantly modulated plaque progression–regression rates across broad categories of residual cardiovascular risk, including patients with low-density lipoprotein cholesterol (LDL-C) levels <70 mg/dL (<1.8 mmol/L).

Puri R, Nissen SE, Shao M et al. Non-HDL cholesterol and triglycerides. Implications for coronary atheroma progression and clinical events. Arterioscler Thromb Vasc Biol 2016; DOI: 10.1161/ATVBAHA.116.307601.
Summary
Comments & References
STUDY SUMMARY
Objective: To define the relationship between achieved non-HDL-C and triglycerides levels with rates of coronary atheroma progression.
Study design: Pooled analysis of 9 clinical trials involving 4,957 patients with coronary disease undergoing serial intravascular ultrasonography
Study population: 4,957 patients (mean ±standard deviation age 57.9±9.2 years, 72% male, 29% with diabetes) with coronary disease. Patients received best evidence-based treatment, as evident by high (on-trial) rates of concomitant treatment with statins (96%), aspirin (94%), beta-blockers (76%), and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (68%).  
Key outcomes:

·       Changes in percent atheroma volume (PAV), as assessed by serial intravascular ultrasonography. Target vessels for imaging had <50% luminal stenosis within a segment of at least 30 mm length. Imaging was performed within the same coronary artery at baseline and at study completion, which ranged from 18 to 24 months.

·       Lipid measurements: non-HDL-C, low-density lipoprotein cholesterol (LDL-C), triglycerides

Major adverse cardiovascular events (MACE, as defined in the individual trials)

Methods:

LOWESS (locally weighted scatter plot smooth) regression was used to visually assess the overall relationship between achieved non-HDL-C and triglycerides levels against changes in PAV. Correlations between variables (change in PAV and on-treatment non-HDL-C, triglycerides and LDL-C) were evaluated with Spearman rank-correlation coefficients. The effects of on-treatment non-HDL-C and triglycerides levels upon coronary atheroma progression were analyzed by stratifying patients according to lower (<100 mg/dL) versus higher (≥100 mg/dL) non-HDL-C levels, and lower (<200 mg/dL) versus higher (≥200 mg/dL) triglycerides levels across differing patient populations (i) on-treatment LDL-C <70 versus ≥70 mg/dL, (ii) on-treatment C-reactive protein <2 versus ≥2 mg/L, (iii) non-diabetic versus diabetic patients.

 Sensitivity analyses were performed to compare the effect of achieved non-HDL-C, triglycerides, and LDL-C levels on MACE rates.

Main results:

·       On-treatment non-HDL-C levels linearly associated with the change in PAV.  This association was stronger than that observed with on-treatment LDL-C levels.

·       The rate of disease progression increased with triglycerides levels >110 mg/dL, with atheroma progression associated with achieved triglycerides levels >200 mg/dL.

·       Lower on-treatment non-HDL-C and triglycerides levels associated with significant PAV regression compared with higher non-HDL-C and triglycerides levels across all levels of LDL-C and C-reactive protein and irrespective of diabetic status (P<0.001 across all comparisons).

·       Sensitivity analyses showed the benefit of lower non-HDL-C and triglycerides on MACE rates. At 24 months, the cumulative incidence of first MACE was significantly greater in those with achieved non-HDL-C levels ≥ median level versus those with non-HDL-C < median value (22.8% versus 14.6%; log-rank p<0.001), as well as those with on-treatment triglycerides ≥ versus <200 mg/dL (23.7% versus 17.5%; log-rank p<0.001).

Authors’ conclusion: Achieved non-HDL-C levels seem more closely associated with coronary atheroma progression than LDL-C. Plaque progression associates with achieved triglycerides, but only above levels of 200 mg/dL. These observations support a more prominent role for non-HDL-C (and possibly triglycerides) lowering in combating residual cardiovascular risk.

COMMENT

The results of this pooled analysis reaffirms the importance of targeting non-HDL-C, which comprises all atherogenic apolipoprotein B-containing lipoproteins, to reduce coronary plaque progression. As shown by this study, the antiatherosclerotic benefit of lower non-HDL-C levels was evident even in patients with well controlled LDL-C levels (<70 mg/dL). Furthermore, the study highlights the importance of elevated triglycerides (>200 mg/dL), irrespective of LDL-C levels, as a contributor to the residual risk of atheroma progression and cardiovascular events. These findings, strengthened by the size of the patient cohort and consistency of methodology, represent the first report of the direct impact of on-treatment non-HDL-C and triglycerides levels on changes in coronary plaque volume over time. 

 For too long, elevated triglycerides, a marker of triglyceride-rich lipoproteins and their remnants, have been neglected as a major risk factor (1). This is despite recent insights from genetic studies which clearly support these lipoprotein particles as causal for atherosclerotic cardiovascular disease (2-4), and as shown by the current study, a contributor to lipid-related residual cardiovascular risk. The rate of coronary disease progression (and, consequently, atherosclerotic risk) seems well established when triglycerides exceed 200 mg/dL; these patients are therefore more likely to derive clinical benefit from a triglyceride-lowering intervention

 Clinical trials aimed at targeting elevated triglycerides against a background of well controlled LDL-C levels, have, however, been less than definitive. Several ongoing or planned trials will be critical in conclusively testing this hypothesis, with novel treatments given as an adjunct to statin in high cardiovascular risk patients. These include the STRENGTH study (with Epanova, a mixture of the free fatty acids docosahexaenoic acid and eicosapentaenoic acid), the REDUCE-IT study (with AMR101, ethyl ester of eicosapentaenoic acid), as well as the PROMINENT study (with the first in class selective peroxisome proliferator-activated receptor modulator pemafibrate) (5-7). Results from these trials are eagerly awaited with the aim of finally resolving the debate regarding the relevance of elevated triglycerides to lipid-related residual cardiovascular risk.  

References

1. Tenenbaum A, Klempfner R, Fisman EZ. Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor. Cardiovasc Diabetol 2014;13:159.

2. Triglyceride Coronary Disease Genetics Consortium, Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, Ricketts SL et al. Triglyceride-mediated pathways and coronary disease: Collaborative analysis of 101 studies. Lancet 2010;375:1634–9.

3. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013;45:1345–52.

4. Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.

5. Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH). ClinicalTrials.gov Identifier: NCT02104817.  https://clinicaltrials.gov/ct2/show/NCT02104817

6. A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. (REDUCE-IT). ClinicalTrials.gov Identifier: NCT01492361.  https://clinicaltrials.gov/ct2/show/NCT01492361

7. Landmark Trial Entitled "PROMINENT" To Explore The Prevention Of Heart Disease In Diabetic Patients With High Triglycerides And Low HDL-C. http://www.prnewswire.co.uk/news-releases/landmark-trial-entitled-prominent-to-explore-the-prevention-of-heart-disease-in-diabetic-patients-with-high-triglycerides-and-low-hdl-c-564982241.html

Key words residual cardiovascular risk; atheroma progression; non-HDL cholesterol; triglycerides; pooled analysis