Raising high-density lipoprotein

The role of lipids in atherosclerosis has

been established over the last 50 years.

The introduction of statin therapy

has revolutionised cardiovascular event

prevention by providing another interven-

tion besides anti-platelet therapy, beta-

blockade and renin–angiotensin system

inhibition that produces a significant

reduction in both acute and chronic

consequences of atherosclerosis. The

large-scale statin studies show that these

drugs that act primarily to reduce low-

density lipoprotein (LDL)-cholesterol

by increasing hepatic LDL-receptor

expression produce 25–35% reduction

in cardiovascular events over 3–5 years

time period (1). These studies, including

the unsuccessful ones (e.g. ALLHAT)

follow a rule, whereby a 1% reduction

in LDL results in a 1% decrease in

cardiovascular events. This rule not only

applies to statins but is also valid for

older interventions that reduce LDL-

cholesterol including bile-acid seques-

trants (resins) and even ileal bypass

surgery (Program Of Surgical Correction

of Hyperlipidemia, POSCH) (2). How-

ever few studies have, as yet, examined

the maximum event reduction that may

be possible with a statin. The only study

that has achieved a 50% reduction in

LDL, the GREACE study, showed a

50% reduction in events confirming the

validity of the rule to higher reductions

(3). However, the log-linear nature of the

relationship of cholesterol with cardio-

vascular events suggests that a law of

diminishing returns may apply to LDL-

cholesterol reduction in the high- vs.

low-dose statin trials currently under

way and manifest as an increase in

the numbers needed to treat. It is also

possible that the maximum event

reduction possible with a statin is

approximately 50% in patients with

polygenic hypercholesterolaemia. These

agents may be more effective in

patients with familial hypercholestero-

laemia who are farther from desired

lipid levels.

This leaves a problem for prevention

strategies. Only 50% of events are

likely to be prevented by LDL reduc-

tion even in spite of optimal ancillary

management as seen in the GREACE

trial. However, the epidemiology of

lipids and atherosclerosis is more com-

plex, with the predictive value of lipids

being expressed not as LDL-cholesterol

alone but as the ratio of total choles-

terol to high-density lipoprotein

(HDL). The epidemiological role of

HDL in protection against athero-

sclerosis is well established and a target

for HDL> 1 mmol/l has been set by

international committees (1). However,

the interpretation of the data from

these studies is complicated by the

inverse relationship between HDL and

triglycerides and the complex allied

changes in particle sizes and distribu-

tions (4,5). HDL clearly predicts

cardiovascular risk. It is closely related

to triglycerides in many patients, and

patients with low HDL and high trigly-

cerides commonly show other lipid and

metabolic abnormalities including the

presence of triglyceride-rich remnant

lipoproteins, small dense LDL (or

IDL), insulin resistance and hyperten-

sion (the metabolic syndrome) (6,7).

This complex interrelationship has com-

plicated the interpretation of trials relat-

ing to HDL-associated cardiovascular

interventions. A number of non-

pharmacological interventions increase

HDL including smoking cessation,

weight loss and increased exercise, and

all these show cardiovascular benefits

but also affect other features of the

metabolic syndrome (1). The role of

alcohol, which increases HDL and tri-

glycerides, is controversial but epide-

miological studies suggest a benefit

with moderate consumption.

Similarly, the trial data with HDL-

raising therapies is complex (Table 1).

Fibrates and nicotinic acid both raise

HDL, but also lower triglycerides,

reduce LDL-cholesterol to varying

extents (nicotinic acid> fibrates), may

also affect lipoprotein (a) (nicotinic

acid) and marginally improve glycae-

mic control (fibrates). The data from

large-scale intervention studies shows

that fibrates reduce events in patient

with low HDL and low LDL

(VA-HIT) (8,9) and maybe also events

in patients with moderate hypercholes-

terolaemia and elevated triglycerides

(Bezafibrate Infarct Prevention Study,

Helsinki Heart Study) (10). Nicotinic

acid reduced events in patients with

moderate hypercholesterolaemia in the

Coronary Drug Project. Data in sub-

groups with diabetes from these trials

shows clear benefit on coronary events

for both fibrates and even for nicotinic

acid (11,12) which many have consid-

ered to cause mild hyperglycaemia (13)

and thus likely increase cardiovascular

risk. In fact, the prime determinants of

cardiovascular risk in patients with type

2 diabetes are LDL and HDL-choles-

terol, while glycaemic control is a weak

risk factor for cardiovascular events and

thus it is not surprising that both inter-

ventions are effective. Additional recent

data on nicotinic acid in patients with

diabetes support the lesser effects of the

new formulations on glycaemic control

(14,15) and further support the end-

point findings from the Coronary

Drug Project of similar benefits in

normoglycaemic and hyperglycaemic

groups (11,16). Since the data are

based on post hoc analysis of interven-

tion trials, formal proof is still required

but will likely be provided in 10,000

primary prevention patients with type 2

diabetes in the fenofibrate intervention

in endpoint lowering in diabetes

(FIELD) study in 2006 (17). This is

likely to demonstrate the equivalence

of fibrates to statins in this patient

group, if other subgroup analyses from

the major statin trials are confirmed.

However, these trials leave unre-

solved the nature of the benefit and its

origin. While VA-HIT is commonly

ª 2004 Blackwell Publishing Ltd Int J Clin Pract, September 2004, 58, 9, 817–819

EDITORIAL d o i : 1 0 . 1 1 1 1 / j . 1 3 6 8 - 5 0 3 1 . 2 0 0 4 . 0 0 3 3 3 . x

supposed to be a HDL-intervention

trial, the largest effects were seen on

triglycerides, remnant lipoprotein mar-

kers (apolipoprotein C3) and LDL-sub-

fraction distributions, and the actual

HDL increment was small (8%), even

given patients with low HDL

(50.93 mmol/l), and in the region of

that achieved in many statin trials

(4–6%) (9). Similar considerations

apply to the Coronary Drug Project

where again the effects are likely due

to an increment in HDL, marked

reduction in triglycerides and some

reduction in LDL. Therefore, there is

a clear scientific need to validate the

HDL hypothesis, but this has not

proved possible until recently, as no

therapeutic agent capable of achieving

a 50% increment in HDL alone was

available. The recent discovery and

clinical trial data on cholesterol ester

transfer protein inhibitors or vaccines

capable of raising HDL by 35–105%

(18,19) suggest that these may now

exist and provide an opportunity for a

pure HDL-raising trial. However,

many are likely to assume that raising

HDL alone is likely to be beneficial,

but this attitude over-simplifies a

complex area. Epidemiological data

for HDL is scarce for levels

>1.5 mmol/l, but limited data on

patients with homozygous CETP

deficiency who commonly have HDL-

cholesterol> 3 mmol/l show that it

may not confer cardiovascular protec-

tion as it may be inactive in reverse

cholesterol transport and that much of

the rise in HDL is actually due to the

presence of an additional HDL-type

lipoprotein particle of unknown func-

tion.

In addition, not all low HDL values

represent dysfunction and hence

increased cardiovascular risk. It is diffi-

cult to study cholesterol turnover from

HDL and given the uptake and re-se-

cretion/re-circulation of HDL in the

liver, studies relying on labelling the

apolipoproteins (e.g. A-1 or A-2) may

give rise to the inaccurate assumption

that cholesterol follows the protein in

this particle, in contrast to apolipopro-

tein B-containing particles where this

assumption is largely true. Point muta-

tions in the alpha-helices of apolipo-

protein A1 can result in HDL-variants

that both have low levels (50.7 mmol/

l) but are associated with markedly

decreased cardiovascular risk as a result

of being hyperfunctional (over-cleared).

The best known of these mutations is

apolipoprotein A-1 Milano. The ability

to produce synthetic HDL as phos-

pholipid-apolipoprotein A1 discs has

enabled a synthetic A-1 Milano to be

made and also a simpler analogue

comprising just the phospholipid disc

and the relevant alpha-helices. When

given intravenously, this agent decre-

ases the burden of coronary ather-

osclerosis in early studies, and thus

confirms the crucial role of HDL in

the regulation of coagulation pathways

(20). If the results of this study are

reproduced on a larger scale, it is likely

to confirm the benefits of acute raising

of HDL to counteract the acute

reduction seen in response to stress

and cytokines. However, HDL infusion

is impractical for longer term interven-

tions, and so this field is not likely to

provide a guide for more chronic

interventions.

As usual, the proof of the concept of

raising HDL is likely to come from

formal clinical trials. The current

evidence base is strong in certain groups

of patients for both fibrates and nico-

tinic acid and both these groups of

agents have pleiotropic actions that

put statins in the shade. The role of

fibrate and nicotinic acid combinations

with statins is beginning to be explored

in clinical trials, which will report by

Table 1 Evidence base for HDL-altering drugs in coronary heart disease (21)

Drug Angiographic benefit End-point trial Change in HDL (%) Effect on CHD events (%)

Fibrate

Bezafibrate BECAIT BIP 16 �8 (Not significant)

LEADER 14 �6 (Not significant)

Clofibrate WHO ? �12 (Not significant)

Gemfibrozil LOCAT HHS 111 �34

VA-HIT 18 �22

Fenofibrate DAIS FIELD 18 Due 2006

Nicotinic acid (niacin)

Nicotinic acid HATS CDP 115 �23

Nicotinic acid1 clofibrate Finnish regression Stockholm ? �36

Novel agents in development

Torcetrapib Not applicable (19) Not applicable 135–105 Not applicable

Apolipoprotein A-1 Milano (ETC-216) IVUS (20) Not applicable Not applicable (Atheroma volume – 4.2%)

BECAIT, bezafibrate coronary atherosclerosis intervention trial; BIP, bezafibrate infarct prevention study; CDP, coronary drug project; DAIS, diabetes

atherosclerosis intervention study; FIELD, fenofibrate intervention for event lowering in diabetes; HATS, HDL atherosclerosis treatment study; HHS, Helsinki

Heart Study; LEADER, lower extremity arterial disease event reduction study; LOCAT, Lopid Coronary Angiography Trial; VA-HIT, Veterans Affairs HDL

Intervention trial; WHO, World Health Organisation European collaborative trial of multifactorial prevention of coronary heart disease; IVUS, intravascular

ultrasound.

818 EDITORIAL

ª 2004 Blackwell Publishing Ltd Int J Clin Pract, September 2004, 58, 9, 817–819

2008. Thus, both monotherapy and

comparator endpoint trials against

these established therapies will have to

be done with newer agents, e.g. CETP

inhibitors, before these are taken up on

a large scale. A warning about believing

in all methods of increasing HDL

already exists in the literature.

Oestrogen-based hormone replacement

therapy raised HDL (and triglycerides),

lowered lipoprotein (a) and LDL-

cholesterol (somewhat) but failed to

demonstrate any benefit on cardio-

vascular events and was actually shown

to transiently increase events through

an unexpected action possibly marked

by elevated c-reactive protein levels.

Thus, proof already exists that not all

modes of raising HDL work. In this

field, as in others, it will be necessary

to prove the benefits of raising HDL

formally and, as usual, it will be only

clinical end points that count.

ANTHONY S. WIERZBICKI

Department of Chemical

Pathology, St Thomas’

Hospital, London, UK

REFERENCES

1 Sacks FM. The role of high-density lipo-

protein (HDL) cholesterol in the preven-

tion and treatment of coronary heart

disease: expert group recommendations.

Am J Cardiol 2002; 90 (2): 139–43.

2 Buchwald H, Boen JR, Nguyen PA et al.

Plasma lipids and cardiovascular risk: a

POSCH report. Program on the Sur-

gical Control of the Hyperlipidemias.

Atherosclerosis 2001; 154 (1): 221–7.

3 Athyros VG, Papageorgiou AA,

Mercouris BR et al. Treatment with

Atorvastatin to the National Cholesterol

Educational Program Goals versus

Usual Care in Secondary Coronary

Heart Disease Prevention. The GREek

Atorvastatin and Coronary-heart-disease

Evaluation (GREACE) Study. Curr Med

Res Opin 2002; 18 (4): 220–8.

4 NairDR,WierzbickiAS,MikhailidisDP.

Time to look beyond just lowering the

serum concentration of low density

lipoprotein–high density lipoprotein

levels are also important. J R Soc Health

2001; 121 (2): 98–101.

5 Wierzbicki AS, Mikhailidis DP. Beyond

LDL-C – the importance of raising

HDL-C. Curr Med Res Opin 2002; 18

(1): 36–44.

6 Wierzbicki AS, Mikhailidis DP, Wray R

et al. Statin-fibrate combination therapy

for hyperlipidaemia: a review. Curr Med

Res Opin 2003; 19: 155–68.

7 Wierzbicki AS, Mikhailidis DP, Wray R.

Drug treatment of combined hyperlipi-

demia. Am J Cardiovasc Drugs 2001; 1

(5): 327–36.

8 Rubins HB, Robins SJ, Collins D

et al. Gemfibrozil for the secondary

prevention of coronary heart disease

in men with low levels of high-density

lipoprotein cholesterol. Veterans Affairs

High-Density Lipoprotein Cholesterol

Intervention Trial Study Group.

N Engl J Med 1999; 341 (6): 410–8.

9 Robins SJ, Collins D, Wittes JT et al.

Relation of gemfibrozil treatment and

lipid levels with major coronary events.

VA-HIT: a randomized controlled trial.

JAMA 2001; 285 (12): 1585–91.

10 Rizos E, Mikhailidis DP. Are high-

density lipoprotein and triglyceride

levelsimportant in secondary

prevention: impressions from the BIP

and VA-HIT trials. Int J Cardiol

2002; 82 (3): 199–207.

11 Canner PL, Furberg CD,

McGovern ME. Niacin decreases

myocardial infarction and total mor-

tality in patients with impaired fasting

glucose or glucose intolerance: results

from the Coronary Drug Project. Cir-

culation 2002; 106 (Suppl. II): 3138

(Abstract).

12 McGovern ME. Use of nicotinic acid in

patients with elevated fasting glucose,

diabetes or metabolic syndrome. Br J

Diabetes Vasc Dis 2004; 4 (2): 78–86.

13 Garg A, Grundy SM. Nicotinic acid as

therapy for dyslipidemia in non-insulin-

dependent diabetes mellitus. JAMA

1990; 264 (6): 723–6.

14 Elam MB, Hunninghake DB, Davis KB

et al. Effect of niacin on lipid and

lipoprotein levels and glycemic control

in patients with diabetes and peripheral

arterial disease: the ADMIT study: a

randomized trial. Arterial Disease

Multiple Intervention Trial. JAMA

2000; 284 (10): 1263–70.

15 Grundy SM, Vega GL, McGovern ME

et al. Efficacy, safety, and tolerability of

once-daily niacin for the treatment of

dyslipidemia associated with type 2

diabetes: results of the assessment of

diabetes control and evaluation of the

efficacy of niaspan trial. Arch Intern Med

2002; 162 (14): 1568–76.

16 Canner PL, Berge KG, Wenger NK

et al. Fifteen year mortality in coronary

drug project patients: long-term benefit

with niacin. J Am Coll Cardiol 1986; 8

(6): 1245–55.

17 Prisant LM. Clinical trials and lipid

guidelines for type II diabetes. J Clin

Pharmacol 2004; 44 (4): 423–30.

18 Wierzbicki AS. Lipid-altering drugs:

the future. Int J Clin Pract 2004 (in

press).

19 Clark RW, Sutfin TA, Ruggeri RB

et al. Raising high-density lipoprotein

in humans through inhibition of

cholesteryl ester transfer protein: an

initial multidose study of torcetrapib.

Arterioscler Thromb Vasc Biol 2004

March; 24 (3): 490–7.

20 Nissen SE, Tsunoda T, Tuzcu EM

et al. Effect of recombinant ApoA-I

Milano on coronary atherosclerosis in

patients with acute coronary syn-

dromes: a randomized controlled

trial. JAMA 2003; 290 (17):

2292–300.

21 Feher MD, Richmond W. Lipids and

Lipid Disorders, 3rd edn. London:

Mosby Wolfe Medical, 2003.

EDITORIAL 819

ª 2004 Blackwell Publishing Ltd Int J Clin Pract, September 2004, 58, 9, 817–819