Low HDL-cholesterol is not a risk factor for recurrent vascular events in patients with vascular disease on intensive lipid-lowering medication

Van de Woestijne AP, van der Graaf Y, Liem AH, et al.
J Am Coll Cardiol. 2013;62:1834-41

Background

Low levels of high-density lipoprotein-cholesterol (HDL-C) are an important risk factor for vascular disease, both in healthy populations [1–3] and in patients with known vascular disease [4–6]. Although these patients are already  intensively treated for risk factors such as high levels of low-density lipoprotein-cholesterol (LDL-C), they are still at a high residual risk for vascular events. Low HDL-C is a risk factor for vascular disease independent of LDL-C [7], even when LDL-C is at target level, and this is still apparent in patients with vascular disease [4,6,8].
Statin trials in patients with coronary artery disease have seen a lack of the inverse relation between HDL-C and risk of vascular events in patients receiving (intensive) statin therapy [9,10,11], albeit with a fixed statin dose, whereas according to current guidelines, LDL-C is treated to target, with various dosages of different statins including combination therapy. As many patients with clinically manifest vascular disease are treated with statins, the residual risk from HDL-C in these patients may be smaller than initially thought.
This study evaluated the vascular risk of low HDL-C in relation to the use and intensity of lipid-lowering medication in patients with clinically manifest vascular diseases. A prospective cohort study was performed in 6,111 patients with manifest vascular disease. Cox proportional hazards models were used to evaluate the risk of HDL-C on vascular events in patients using no, usual dose, or
intensive lipid-lowering therapy.

Main results

• New vascular events (myocardial infarction, stroke, or vascular death) occurred in 874 subjects during a median follow-up of 5.4 years (interquartile range: 2.9 to 8.6 years).
• In patients not using lipid-lowering medication at baseline (n = 2,153), a 0.1 mmol/l increase in HDL-C was associated with a 5% reduced risk for all vascular events (hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.92 to 0.99).
• In patients on usual dose lipid-lowering medication (n = 1,910) there was a 6% reduced risk (HR: 0.94; 95% CI: 0.90 to 0.98).
• However, in patients using intensive lipid-lowering treatment (n = 2,046), HDL-C was not associated with recurrent vascular events (HR: 1.02; 95% CI: 0.98 to 1.07) irrespective of LDL-C level.
• In quartiles of higher HDL-C, the risk of vascular events was lower in patients on usual dose lipid-lowering therapy compared with the lowest HDL-C quartile.
• For patients on intensive lipid-lowering therapy, the overall risk for vascular events was lower compared with patients using no or usual dose lipid-lowering, but there was no relation between HDL-C and vascular risk in that group.

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Conclusion

HDL-C levels are related to the risk of new cardiovascular events in patients with clinically manifest vascular disease treated with usual dose lipid-lowering therapy but not in patients treated with intensive lipid-lowering medication, irrespective of LDL-C.

Editorial comment [12]

This study suggests that the measurement of HDL-C in patients with established atherosclerotic cardiovascular disease treated with intensive LDL-C lowering no longer predicts future cardiovascular events. The “HDL hypothesis” states that raising HDL-C prevents cardiovascular disease, but this has been severely challenged of late. Current guidelines for the prevention and treatment of cardiovascular disease should continue to focus on LDL-C as the major therapeutic target. Non–HDL-C (i.e., the sum of apo B-containing lipoproteins) or apo B itself are solid therapeutic targets as well. There is little support from clinical trials to attempt to raise HDL-C pharmacologically. To date, the trial evidence is at best neutral; at worst, there is evidence of harm. The link of causality between HDL-C and cardiovascular disease might have to be rethought . Better biomarkers of HDL function have to be developed and tested in clinical trials.
For the time being, the concept of HDL-C as representing an important proportion of residual cardiovascular risk in patients on appropriate statin dosage is not well supported by data.

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References

1. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 1986;256:2835–8.
2. Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein (a), apolipoproteins A-I and B, and HDL density subfractions-The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108–13.
3. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000.
4. Hajer GR, van der Graaf Y, Bots ML, et al. Low plasma HDL-c, a vascular risk factor in high risk patients independent of LDL-c. Eur J Clin Invest 2009;39:680–8.
5. Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990;322:1700–7.
6. Sacks FM, Tonkin AM, Craven T, et al. Coronary heart disease in patients with low LDL-cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors. Circulation 2002;105:1424–8.
7. 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;102:1–34K.
8. Seo SM, Choo EH, Koh YS, et al. High-density lipoprotein cholesterol as a predictor of clinical outcomes in patients achieving lowdensity lipoprotein cholesterol targets with statins after percutaneous coronary intervention. Heart 2011;97:1943–50.
9. Ridker PM, Genest J, Boekholdt SM, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet 2010;376: 333–9.
10. Sacks FM, Moye LA, Davis BR, et al. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events trial. Circulation 1998;97:1446–52.
11. Ray KK, Cannon CP, Cairns R, Morrow DA, Ridker PM, Braunwald E. Prognostic utility of apoB/AI, total cholesterol/HDL, non-HDL cholesterol, or hs-CRP as predictors of clinical risk in patients receiving statin therapy after acute coronary syndromes: results from PROVE IT-TIMI 22. Arterioscler Thromb Vasc Biol 2009;29:424–30.
12. Genest J. HDL and Residual Cardiovascular Risk: De minimis non curat medicus? Or: The COURAGE to be SMART.
J Am Coll Cardiol. 2013;62:1842-44