European Heart Journal (2004) 25, 716–719
Editorial
Treating low HDL-cholesterol in
normocholesterolaemic patients with
coronary disease: statins, fibrates or horses
for courses?
University of Western Australia, School of Medicine and Pharmacology, Royal Perth Hospital Unit, GPO Box X2213,
Perth WA 6847, Australia
This editorial refers to “Effects of pravastatin on
coronary events in 2073 patients with low levels of
both low-density lipoprotein cholesterol and highdensity lipoprotein cholesterol: results from the LIPID
study” by D. Colquhoun et al. on page 771
A low plasma concentration of high-density lipoprotein
(HDL)-cholesterol is a powerful independent risk factor
for coronary heart disease (CHD). This notion is supported by consistent evidence from epidemiological,
clinical and experimental studies.1 Low plasma HDLcholesterol is frequently encountered in patients with
CHD, either as part of the ‘atherogenic-lipid-triad’ seen
in central obesity or type 2 diabetes,2 or as an isolated
lipoprotein abnormality of genetic origin. At present, the
expert recommendation is that CHD patients who have
appropriately modified their lifestyle and who have an
optimal low-density lipoprotein (LDL)-cholesterol (<2.6
mmol/L) and low HDL-cholesterol (<1.05 mmol/L) be
treated with HDL modifying pharmacotherapy, such as a
fibrate or nicotinic acid.3 In this issue, Colquhoun et al.
present a subanalysis from the Long-term Intervention
with Pravastatin in Ischaemic Disease (LIPID) study asserting that these patients could equally be treated with
a statin,4 a drug usually employed to lower elevated
plasma LDL-cholesterol levels.
The LIPID trial is one of the largest secondary prevention trials confirming the cardiovascular benefit of
treating CHD patients with a statin, specifically pravastatin 40 mg daily. In the present study, Colquhoun
et al. selected a subgroup with plasma lipid entry criteria similar to volunteers in the Veterans Affairs High-
* Correspondence to: Fax: þ61-8-9224-0246.
E-mail address: [email protected] (G.F. Watts).
doi:10.1016/j.ehj.2004.03.013.
Density Lipoprotein Intervention Trial (VA-HIT),5 a secondary prevention trial demonstrating the benefits of
gemfibrozil (1200 mg/day) on both coronary and cerebrovascular events in CHD patients with normocholesterolaemic dyslipidaemia. Of the original 9014 LIPID
subjects, 2073 were accordingly selected with entry
LDL-cholesterol <3.6 mmol/L, triglyceride <3.4 mmol/
L and HDL <1.0 mmol/L. In this subgroup, the relative
risk reduction with pravastatin in the pre-specified primary endpoint (CHD death and non-fatal myocardial
infarction) was 27%, with a corresponding absolute risk
reduction of 4%. These benefits of pravastatin were
associated with a 29% decrease in plasma LDL-cholesterol, a 9% decrease in triglycerides and a 6% increase in
HDL-cholesterol. In the VA-HIT, the corresponding relative and absolute risk reductions with gemfibrozil in a
similar primary endpoint were 22% and 4.4%, respectively; there was also no change in plasma LDL-cholesterol, but triglycerides fell significantly by 31% and
HDL-cholesterol increased by 6%. From these collective
data, the authors recommend that pravastatin be considered as first-line therapy in CHD patients with low
plasma levels of both HDL and LDL-cholesterol. The
study, however, raises several important issues concerning the management of this type of dyslipidaemia in
patients with CHD, but first one has to question the
validity of the analyses.
The LIPID subgroup analysis component of the study
is valid on several grounds.6 Although apparently a posthoc study, the authors apparently based their analysis
on an a priori hypothesis and on a substantial sample
size. The magnitude of the treatment effect reported
with pravastatin is clinically important, the number
needed to treat to prevent a major CHD event over 6
years being 25 patients;4 the results are also biologically plausible and consistent with data from other
statin trials. By contrast, the comparison made with
0195-668X/$ - see front matter c 2004 Published by Elsevier Ltd on behalf of The European Society of Cardiology.
doi:10.1016/j.ehj.2003.12.024
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Gerald F. Watts*
Editorial
consistent with the positive angiographic results with
simvastatin plus niacin in the HDL Atherosclerosis
Treatment Study (HATS).14
Along with central obesity, hypertriglyceridemia,
hypertension and insulin resistance, low HDL-cholesterol is a cardinal feature of the metabolic syndrome,2;3
which was apparently over-represented in VA-HIT and
under-represented in LIPID. A recent subgroup analysis
from VA-HIT15 has shown that in insulin resistant subjects, including type 2 diabetics, gemfibrozil decreased
the relative and absolute risk of major cardiovascular
events by 28% and 8.4%, respectively; these effects
were significantly greater than in insulin sensitive subjects and are supported by data from the Helsinki Heart
Study.16 Intriguingly, in the insulin resistant subjects
the benefit was also reported to be independent in
changes in plasma lipids and lipoproteins, including increase in plasma HDL-cholesterol. Hence, it appears
that in VA-HIT most of the benefits with gemfibrozil5
were seen in the subgroup with the metabolic syndrome, an issue that was not addressed by the LIPID
investigators. The mechanism for this specific effect of
gemfibrozil and other fibrates may be due to activation
of peroxisome proliferator activated receptor-alpha
(PPAR-a), with decreased inflammatory signalling, enhanced fibrinolysis and improvement in endothelial
function,12 as well as an increase in the rate of reverse
cholesterol transport not reflected by changes in plasma
HDL-cholesterol concentrations.17 By contrast to fibrate
trials, no statin trial has hitherto reported statistically
significant cardiovascular benefits in subjects with the
metabolic syndrome; this includes a subgroup analysis
of 38% of the study population with this disorder in the
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).18
HPS did, however, show that simvastatin significantly
decreased the pre-specified coronary endpoint in type 2
diabetic patients with and without CHD.19 Additional
subgroup analyses from the LIPID20 and Cholesterol and
Recurrent Events (CARE)21 studies have suggested a favourable impact of pravastatin on expanded cardiovascular endpoints (including re-vascularizations) in
subjects with diabetes or impaired glucose tolerance,
but by contrast to VA-HIT no significant effect has been
reported on CHD deaths in these patients. In VA-HIT the
absolute risk reduction in the primary endpoint (CHD
deaths and non-fatal myocardial infarction) was twofold
greater than in statin trials in diabetic patients with
low-to-normal LDL-cholesterol levels. Collectively, the
implication here is that in metabolic syndrome patients
with low HDL and LDL-cholesterol a fibrate may be
more appropriate first-line therapy than a statin,
thereby qualifying a principal assertion of the LIPID
investigators.4
In aggregate, this new study from LIPID supports using
a statin to treat CHD patients with low HDL-cholesterol
and normal-to-low LDL-cholesterol levels. However, if
low HDL-cholesterol is a constituent of the metabolic
syndrome, and LDL and non-HDL cholesterol are not elevated, a better first option may be a fibrate. Using
statin or fibrate monotherapy should fundamentally not
be considered as mutually exclusive, however. A more
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VA-HIT5 is less justified in that the populations in the
two trials are disparate. The LIPID subjects, for example, comprise significantly fewer diabetics, obese subjects and smokers, and their corresponding mean
plasma levels of LDL-cholesterol and non-HDL-cholesterol were higher than VA-HIT subjects; also, no women
were included in VA-HIT.5 As discussed later, the differences in the proportion of diabetic and metabolic
syndrome subjects between the trials could in particular be of major significance. The higher mean LDL and
non-HDL-cholesterol in the LIPID subgroup would also
have potentially biased treatment effects in favour of
pravastatin. It is noteworthy here that the authors also
reported that pravastatin did not decrease CHD events
in another subgroup with mean LDL cholesterol more
comparable to VA-HIT. To be valid, then, the cardiovascular effects of pravastatin and gemfibrozil in CHD
patients with low LDL and HDL-cholesterol should to be
compared prospectively within the same population.
These new findings from LIPID are supported by a recent meta-analysis from the Prospective Pravastatin
Pooling Project,7 by the Heart Protection Study (HPS)
results,8 and by the angiographic findings in the Lipoprotein and Coronary Atherosclerosis Study (LCAS),9 as
well as by the Air Force/Texas coronary atherosclerosis
prevention study (TexCAPS).10 The data in HPS with
simvastatin and in LCAS with fluvastatin in CHD patients
with normal LDL and low HDL-cholesterol points to a
class effect of statins in this population. In general, both
secondary and primary prevention trials have demonstrated that the efficacy of statin treatment is greatest
in subjects at high risk of CHD, including those with low
HDL-cholesterol. Similar findings also apply to fibrate
trials, although the studies carried out with these agents
are significantly fewer in number.
Potential mechanisms explaining the benefits of statins in the reference population could involve reduction
in both plasma LDL and remnant lipoproteins, elevation
in HDL-cholesterol and pleiotropic actions,11 including
anti-inflammatory, anti-thrombotic and antioxidant effects and improvement in endothelial function. Because
of these multiple effects of statins, which to some extent
are shared with fibrates,12 it is impossible to resolve in
the present analysis whether raising HDL per se decreases the risk of CHD. It is noteworthy, however, that a
previous analysis from the parent LIPID population
showed that 80% of the benefit on total coronary events
could be explained by an effect of pravastatin on plasma
LDL-cholesterol, HDL-cholesterol and triglycerides,13 indicating a lesser contributory role of pleiotropic mechanisms. Whether this also obtains with the present LIPID
subgroup remains to be demonstrated. While the reductions in LDL and non-HDL-cholesterol were impressive
in this study, HDL-cholesterol only increased modestly
with pravastatin and, importantly, the event rate (11.9%)
in low HDL patients still remained higher than in placebo
treated patients with HDL-cholesterol >1.0 mmol/L
(10.4%).4 This, together with the finding that pravastatin
did not increase the mean HDL-cholesterol group above
1.0 mmol/L, has implications for the potential of using a
statin together with specific HDL regulating therapy,
717
718
References
1. Sacks FM. Expert Group on HDL cholesterol. The role of high-density
lipoprotein (HDL) cholesterol in the prevention and treatment of
coronary heart disease: expert group recommendations. Am J Cardiol
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2. Reaven G. Metabolic syndrome: pathophysiology and implications for
management of cardiovascular disease. Circulation 2002;106:
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3. Third Report of the National Cholesterol Education Program (NCEP).
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4. Colquhoun D, Keech, Hunt D et al. Effects of pravastatin on coronary
events in 2073 patients with low levels of both low-density lipoprotein cholesterol and high-density lipoprotein cholesterol: results
from the LIPID study. Eur Heart J 2004;25:771–7.
5. Rubins HB, Robins SJ, Collins D et al. for the Veterans Affairs HighDensity Lipoprotein Cholesterol Intervention Trial Study Group.
Gemfibrozil for the secondary prevention of coronary heart disease
in men with low levels of high-density lipoprotein cholesterol. New
Engl. J. Med. 1999;341:410–8.
6. Oxman AD, Guyatt GH. A consumer’s guide to subgroup analyses. Ann
Int Med 1992;116:78–84.
7. Sacks FM, Tonkin AM, Shepherd J et al. for The Prospective
Pravastatin Pooling Project Investigators Group. The effect of
pravastatin on coronary disease events in subgroups defined by
coronary risk factors. Circulation 2000;201:1893–900.
8. Heart Protection Study Collaborative Group. MRC/BHF heart
protection study of cholesterol-lowering with simvastatin in 5963
people with diabetes: a randomised placebo-controlled trial.
Heart Protection Study Collaborative Group. Lancet 2003;361:
2005–2016.
9. Ballantyne CM, Herd A, Ferlic MS et al. Influence of low HDL on
progression of coronary artery disease and response to fluvastatin
therapy. Circulation 1999;99:736–43.
10. Gotto AM, Whitney E, Stein EA et al. Relation between baseline and
on-treatment lipid parameters and first acute major coronary events
in the Air Force/Texas coronary atherosclerosis prevention study
(AFCAPS/TexCAPS). Circulation 2000;101:477–84.
11. Rosenson RS, Tangney CC. Antiatherothrombotic properties of
statins. Implications for cardiovascular event reduction. JAMA
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12. Fruchart JC, Duriez P, Staels B. Peroxisome proliferator activated
receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. Curr Opin
Lipidol 1999;10:245–57.
13. Simes RJ, Marschner IC, Hunt D et al. Relationship between lipid
levels and clinical outcomes in the long-term intervention with
pravastatin in ischemic disease (LIPID) trial. Circulation
2002;105:1162–9.
14. Brown BG, Zhao X-Q, Chait A et al. Simvastatin and niacin,
antioxidant vitamins, or the combination for the prevention of
coronary disease. New Engl J Med 2001;345:1583–92.
15. Robins SJ, Rubins HB, Faas FH et al. The veterans affairs
HDL intervention trial (VA-HIT). Insulin resistance and cardiovascular events with low HDL cholesterol. Diabetes Care 2003;26:
1513–7.
16. Tenkanen L, Manttari M, Manninen V. Some coronary risk factors
related to the insulin resistance syndrome and treatment with
gemfibrozil. Experience from the Helsinki Heart Study. Circulation
1995;92:1779–85.
17. Watts GF, Barrett PHR, Ji J et al. Differential regulation of
lipoprotein kinetics by atorvastatin and fenofibrate in subjects with
the metabolic syndrome. Diabetes 2003;52:803–11.
18. Sever PS, Dahlof B, Poulter NR et al. Prevention of coronary and
stroke events with atorvastatin in hypertensive patients who have
average of lower-than-average cholesterol concentrations, in the
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19. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 20 536 high-risk
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important issue arising from this study is whether there is
incremental benefit from adding a fibrate to a statin in
the low HDL patient with CHD. This can only be resolved
in clinical endpoint trials, but no such trials have hitherto
been reported; one currently underway is the Action to
Control Cardiovascular Risk in Diabetes (ACCORD)
study,22 which is testing the efficacy of adding fenofibrate to simvastatin. However, combination statin-fibrate therapy is being commonly employed in clinical
practice, with due attention to minimising and monitoring the risk of myositis. Importantly, fenofibrate is
less likely to interact adversely with statins than gemfibrozil. Fish oil supplementation in combination with a
statin is another potentially effective and safe option.
Any therapy in CHD patients directed at elevating low
plasma HDL-cholesterol, whether as an isolated abnormality or as part of the metabolic syndrome, needs to be
accompanied by behavioural modifications that include
weight loss, avoiding high-carbohydrate intake, increasing physical activity, improving glycaemic control,
smoking cessation and reviewing potential aggravating
medications (e.g. beta-blockers, progestational agents).
All CHD patients with low HDL-cholesterol should also
evidently receive intensive management of all cardiovascular risk factors beyond dyslipidaemia.
One difficulty with HDL elevating therapy at present is
that there is no exact definition of the optimal plasma
HDL-cholesterol level, although there is a consensus that
<1.05 mmol/L is undesirable in patients with CHD or CHD
equivalents.3 For the metabolic syndrome and type 2 diabetes a therapeutic target of >1.2 mmol/L, or greater,
could be recommended,22 but this requires verification
and endorsement by wider expert bodies. Elevating
plasma HDL-cholesterol concentration from a low level to
a level >1.2 mmol/L can be difficult with conventional
approaches. Nicotinic acid is a powerful HDL raising
agent, but clinical experience shows that many patients
cannot tolerate it owing to flushing and palpitations, and
there may be problems with dysglycaemia and hyperuricaemia; no clinical trials have also been reported in low
HDL patients with the metabolic syndrome. New HDL elevating agents, such as cholesteryl-ester transfer protein
inhibitors, can substantially increase plasma HDL-cholesterol concentration by up to 60%,23 but the efficacy of
these drugs either as monotherapy or in combination with
statins and fibrates require further investigation. Other
futuristic HDL-based therapies include use of small molecules that can increase the expression of HDL apoA-I or
upregulate ABCAI transporters in macrophages, or the
intravenous delivery of recombinant HDL apoA-I, such as
apoAI Milano, a particularly promising approach recently
shown to regress coronary atherosclerosis in patients with
acute coronary syndromes.24 As with existing treatments,
all these new approaches will need to be formally tested
in clinical endpoint trials. Finally, an important therapeutic target for future drug discovery is the enhancement of reverse cholesterol transport irrespective of
changes in plasma HDL-cholesterol concentrations,25 but
this innovative concept will also need to be vigorously
researched and validated.
Editorial
Editorial
individuals: a randomised placebo-controlled trial. Heart Protection
Study Collaborative Group. Lancet 2002;360:7–22.
20. Keech A, Colquhoun D, Best J et al. Result from the LIPID trial.
Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose.
Diabetes Care 2003;26:2713–21.
21. Goldberg RB, Mellies MJ, Sacks FM et al. Cardiovascular events and
their reduction with pravastatin in diabetic and glucose-intolerant
myocardia infarction survivors with average cholesterol levels.
Circulation 1998;98:2513–9.
22. Haffner SM, Goldberg RB. New strategies for the treatment of
Diabetic Dyslipidemia. Diabetes Care 2002;25:1237–9.
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23. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF et al. Efficacy and
safety of a novel cholesteryl ester transfer protein inhibitor JTT-705,
in humans: a randomized phase II dose–response study. Circulation
2002;105:2159–65.
24. Nissen SE, Tsunnoda T, Murat Tuzcu E et al. Effect of recombinant
ApoA-l Milano on coronary atherosclerosis in patients with acute
coronary syndromes: a randomized controlled trial. JAMA 2003;290:
2292–300.
25. von Eckardstein A, Nofer J-R, Assmann G. High density lipoproteins and arteriosclerosis: role of cholesterol efflux and reverse
cholesterol transport. Arterioscler Thromb Vasc Biol 2001;21:
13–27.
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