Physicians' Academy for Cardiovascular Education

HDL-C and residual cardiovascular risk in relation to lipid-lowering medication

Literature - Van de Woestijne et al. JACC 2013 - JACC 2013

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


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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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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J Am Coll Cardiol. 2013;62:1842-44