HDL particle concentration may better predict CVD event risk than HDL-c
High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy.
Mora S, Glynn RJ, Ridker PM
Circulation. 2013 Sep 10;128(11):1189-97. doi: 10.1161/CIRCULATIONAHA.113.002671
BackgroundThe residual CVD risk in statin-treated individuals has driven interest in therapeutic interventions targeted at modulating HDL-c levels. Both experimental studies and large-scale trials have explored this option. To date raising HDL-c have not yielded a reduction of CV events [1-3] or atherosclerosis .
It is possible that HDL-c is not the best clinical measure of HDL. An analysis of Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) challenged the long-standing idea that low HDL-c is an important risk factor for residual risk among statin-treated patients [5,6]. In JUPITER, on-treatment HDL-c was not predictive of residual risk among statin-treated individuals, while HDL-c did have predictive value among those taking placebo. On-treatment apolipoprotein A-I (apoA-I) and triglycerides were also found to be of no use for prediction of residual risk .
Chemically measured HDL-c evaluates the cholesterol carried by HDL particles. This may not fully reflect HDL-related cardioprotection. HDL function, size or the concentration (number) of HDL particles (HDL-P) have therefore been proposed as better clinical markers of HDL. Very little is known about the impact of statin therapy on measures of HDL other than HDL-c.
This paper reports the evaluation of whether residual CVD risk is better explained by HDL-P in comparison with HDL-c, making use of JUPITER data. In JUPITER, potent statin therapy or placebo was randomly assigned in a primary prevention population that achieved very low LDL-c levels.
- HDL-P correlated only moderately with HDL-c at baseline (r=0.55, P<0.0001) and after 1 year of statin therapy (r=0.63, P<0.0001). HDL-P correlated more strongly with apoA-I at baseline (r=0.69, P<0.0001) and after 1 year of statin treatment (r=0.72, P<0.0001).
- Rosuvastatin 20 mg/d decreased LDL-c by 51 mg/dL (49%) and increased HDL-c by 3 mg/dL and apoA-I by 3 mg/dL. HDL size was increased by 0.1 nm, and HDL-P by 1.3 µmol/L (P<0.0001 for all).
- Among rosuvastatin-allocated individuals, baseline HDL-P was statistically significantly associated with CVD events (0.78, 95%CI: 0.61-0.99 per 6.32 µmol/L), while no significant associations were seen for baseline HDL-c, apoA-I or HDL size.
On-treatment HDL-P in rosuvastatin-treated individuals was significantly and somewhat stronger associated with CVD (0.73, 95%CI: 0.57-0.93, P=0.01) than HDL-c (0.82, 95%CI:0.63-1.08, P=0.16) or apoA-I (0.86, 95%CI: 0.67-1.10, P=0.22).
- Overall, similar patterns of associations were seen for women and men.
- Further adjustment for hsCRP and LDL particle concentration did not alter the association of HDL-P with CVD.
ConclusionThis study suggests that HDL-P may be a better marker of residual risk than HDL-c or apoA-I among individuals who receive potent statin therapy to achieve very low LDL-c levels. HDL-P appears to be less correlated with factors that affect the association of HDL-c with CVD. Also, HDL-P may better reflect greater reverse cholesterol transport capacity and other functional properties than does HDL-c.
Since this study was observational and thus only hypothesis-generating, future studies will need to examine the various functional properties of HDL in relation to HDL-P, HDL size and other measures of HDL and how these are impacted by therapies targeting HDL.
1. Barter PJ, Caulfield M, Eriksson M, et al. ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–2122.
2. Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–2267.
3. Schwartz GG, Olsson AG, Abt M, et al. dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–2099.
4. Nissen SE, Tardif JC, Nicholls SJ, et al; ILLUSTRATE Investigators. Effect of torcetrapib on the progression of
coronary atherosclerosis. N Engl J Med. 2007;356:1304–1316.
5. Barter P, Gotto AM, LaRosa JC, et al; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301–1310.
6. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 suppl):1K–34K.
7. Mora S, Glynn RJ, Boekholdt SM, et al. On-treatment non-high-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and lipid ratios in relation to residual vascular risk after treatment with potent statin therapy: JUPITER (Justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). J Am Coll Cardiol. 2012;59:1521–1528.