Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis

Briel et al (1) have carried out an extensive meta-analysis,
comprising nearly 300,000 participants in randomized clinical trials of
lipid modifying therapies, which failed to identify a statistically
significant association between changes in high-density lipoprotein-
cholesterol (HDL-C) levels and cardiovascular outcomes. The results of
this analysis contradict data from all major fibrate trials, that have
consistently shown a significant association between on-treatment HDL-C
increments and major reductions in cardiovascular events in both primary
and secondary prevention settings (2-4). These apparently conflicting data
can be attributed to important differences in the selected populations
among the studies. Briel et al, have chosen to focus their analysis mainly
on statin trials (n=62), which were designed to reduce LDL-C in patients
with moderately to high baseline LDL-C levels and a mean baseline HDL-C
that was in the normal range (47 mg/dL), whereas fibrate trials evaluated
the benefit of lipid modifying therapies among high-risk patients with the
common raised triglycerides-low HDL-C dyslipidaemia. Accordingly, the
results of the present meta-analysis are biased to a patient population
within which lipid modifying therapies resulted in major on-treatment LDL-
C reductions and relatively minor HDL-C increments.

To evaluate the benefit associated with on-treatment HDL-C
increments, we have carried out a subanalysis of the Bezafibrate
Infarction Prevention (BIP) Trial, comprising 3020 coronary heart disease
patients with the raised triglycerides-low HDL-C dyslipidaemia (2). Our
data demonstrate that, in this high-risk patient subset, 5 mg/dL
increments in HDL-C were independently associated a significant 27%
(p<0.001) reduction in cardiac mortality, whereas on-treatment
reductions in LDL-C did not contribute to outcome after adjustment for HDL
-C changes. The long-term survival benefit associated with of HDL-C
modification was also substantiated in an extended 16-year follow-up study
of the BIP trial (5). Furthermore, in a recent analysis of the BIP
population (6), we have shown that the benefit of raising HDL-C is related
to baseline serum levels of LDL-C. Thus, HDL-C modification was associated
with an enhanced survival benefit among patients with low baseline LDL-C
(< 130 mg/dL), whereas a significant benefit of LDL-C modification was
evident only among patients with elevated baseline LDL-C (>130 mg/dL)
(6). These results further demonstrate the substantial benefit associated
with increasing HDL-C, provided appropriate selection of patients and
therapeutic modalities.

We are concerned that the findings by Briel et al may provide
erroneous and misleading implications for an important proportion of
currently treated patients with the common raised triglycerides-low HDL-C
dyslipidaemia, who have a high risk for major cardiac events even when
their LDL-C levels are in the normal- or low-range (7). This important
subset of patients should receive a more comprehensive lipid modifying
therapeutic approach, designed also to raise HDL-C and reduce
triglycerides, rather than a narrow approach that is based solely on LDL-c
modification as suggested by Briel et al.

References

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P, Blechacz B, Bassler D, Wei X, Sharman A, Whitt I, Alves da Silva S,
Khalid Z, Nordmann AJ, Zhou Q, Walter SD, Vale N, Bhatnagar N, O'Regan C,
Mills EJ, Bucher HC, Montori VM, Guyatt GH. Association between change in
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Kastelein JJ, Bittner V, Fruchart JC; Treating to New Targets
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Competing interests:
None declared