Low HDL-cholesterol: common and under-treated, but which drug to use?

nail. I believe it is very clear in the

paper that patients should be offered

medical intervention first.

Now that I have laid out this rather

dismal picture, what is the answer?

How about focusing on education of

the PCP? Let us focus on the prostate

for what it is; an underappreciated

gland that should not be so misunder-

stood. If the PCP becomes comfort-

able, then they can relay that to the

patients and it is a win-win. And

maybe, more uniform and earlier

intervention will lead to less complica-

tions of EP, such as acute urinary

retention and decreased quality of life.

My friends have heard this educa-

tion issue from me several times over

the last few years. Urological health

starts in the office of the PCP, and

only when it is refractory should it go

the urologist. This is not only for EP,

but also for overactive bladder, hypo-

gonadism, interstitial cystitis and erec-

tile dysfunction. I hate to get on the

soapbox, but these diseases are not

surgical in the early phases.

Maybe, exposure to urological

health can become a more integral part

of the core curriculum for the PCP.

Or perhaps, there should be more

emphasis on postgraduate or after resi-

dency training. We can set up a Uro-

School that has, as its mission, the

intent on basic urological training for

the PCP. We can call it P.U. (now,

I meant that one). My musical friend

at Harvard is now a very successful

paediatric urologist, but maybe we can

get him to coach the cheer squad.

M. T. Rosenberg

Mid Michigan Health Centers,

Jackson, MI, USA

R E F E RE N C E S

1 Kaplan S, Naslund M. Public, patient,

and professional attitudes towards the

diagnosis and treatment of enlarged

prostate: a landmark national US sur-

vey. Int J Clin Pract 2006; 60: 1157–

65.

2 Kursh ED. Evaluation and treatment

of benign prostatic hypertrophy. In:

Jeannette MP, ed. Essential Urology: A

Guide to Clinical Practice. Totowa, NJ:

Humana Press, 2004: 191–202.

3 American Urological Association Web-

site, available at http://www.auanet.org/

about/content/membersprofile.pdf, acc-

essed May 2006.

Low HDL-cholesterol: common and under-treated, but whichdrug to use?

The epidemiology of cardiovascular

risk and atherosclerosis has been estab-

lished in large studies (1–3). All show

that risk of myocardial infarction is

related to the ratio of total: high-den-

sity lipoprotein-cholesterol (HDL-C)

measured either directly or indirectly

by concentrations of their principal

protein components (apolipoprotein

B: A-I ratio). The combined lipid risk

factors accounted for up to 49% of

the population attributable risk for

coronary atherosclerosis in the

INTERHEART study (1).

Low HDL-C forms one of the defi-

ning components of the metabolic syn-

drome in all the definitions (4,5). Thus

not only is HDL-C associated with

hypertriglyceridaemia, dysglycaemia,

abdominal obesity and the risk of cor-

onary heart disease (CHD), it is also

associated with increased risks of diabe-

tes (6). The phenomenon of low HDL-

C as a risk factor for new diabetes is

under-recognised but again HDL-C is

one of the components of the risk algo-

rithms for prediction of type 2 diabetes

based on the Insulin Resistance and

Atherosclerosis Study (7).

The functions of HDL-C are mul-

tiple and its biochemistry is complex

(8). HDL-C comprise multiple types

of particles that differ in apolipopro-

tein content though all HDL-C parti-

cles contain 1–4 and usually two

apolipoprotein A-I molecules. Numer-

ous subspecies exist differing in associ-

ated common proteins e.g.

apolipoprotein A-II as well as in size

(HDL 2 vs. HDL 3) but also more

subtly in the other 20–30 proteins

associated with HDL-C including apo-

lipoproteins E, C-III, C-I, H (b-2 gly-

coprotein I), J (clusterin), L and M.

Enzymes associated with HDL-C

include the antioxidant paraoxonase,

phospholipases including phospholi-

pase A2 and fatty acid metabolising

enzymes including platelet activating

factor (PAF)1 hydrolase. HDL-C is

involved in reverse cholesterol trans-

port, is an antioxidant, anticoagulant,

anti-inflammatory and has direct anti-

atherosclerotic effects when infused

into animal models. Some hyperfunc-

tional mutations (e.g. apolipoprotein

A-I Milano) are found in man and a

recent trial of ApoA-I Milano in

phospholipid discs has found that only

five infusions given weekly induce

regression of atherosclerosis on intra-

vascular ultrasound after one 6 weeks

(9). Then effects are comparable with

those seen in the REVERSAL trial

comparing high dose atorvastatin

(80 mg) with pravastatin 40 mg after

18 months of treatment (10).

Thus there is good evidence that

HDL-C should form an important

target for therapy. The question then

arises at what level should this be war-

ranted? The exact HDL-C target is

controversial as all the evidence is

observational and based on epidemiol-

ogy rather than intervention trials. A

EDITORIAL 1149

ª 2006 The AuthorsJournal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, October 2006, 60, 10, 1147–1156

number of epidemiological have inves-

tigated the distribution of HDL-C.

Much of the data used for recommen-

dations is derived from older epidemi-

ological studies such as Framingham

and the Multiple Risk Factor Inter-

vention Trial (3). Pronounced differ-

ences were seen in HDL-C between

the sexes and levels were noted to fall

with age with an extra reduction

because of the menopause in women.

Consensus and guideline groups have

reviewed this evidence and the limited

trial data on drugs having some effect

on raising HDL-C (fibrates or nico-

tinic acid) and suggested that patients

with a HDL-C 01 mmol/l (40 mg/

dl) should receive extra attention and

possible drug treatment (11,12).

Other groups have suggested differen-

tial cutoffs at 1.0 mmol/l (40 mg/dl)

and 1.2 mmol/l (50 mg/dl) for men

and women respectively (12).

In this issue Farnier et al. report the

results of the Etude de Cholesterol

HDL en observationne (ECHOS)

study in France that evaluated the pre-

valence of low HDL-C in a cross-sec-

tional study of 5232 patients with

other cardiovascular risk factors (13).

At a cutoff of 0.9 mmol/l (35 mg/dl)

8.7% of the population had low

HDL-C while 26.9% had low HDL-

C by the National Cholesterol Educa-

tion Programme adult treatment panel

3 (NCEP-ATP3) criteria [1.0 mmol/l

(40 mg/dl) male; 1.2 mmol/l (50 mg/

dl) female]. Low HDL-C was associ-

ated with previous cardiovascular dis-

ease (CVD) rather than abdominal

obesity or hypertriglyceridaemia or

type 2 diabetes. In another pan-Euro-

pean survey of 8545 with dyslipidae-

mia from 11 countries, very low

HDL-C [00.90 mmol/l (035 mg/

dl)] occurred in 14% of patients

whether treated or not with lipid-low-

ering drugs (14). By NCEP-ATP3 cri-

teria low HDL-C was found in 40%

of women and 33% of men. Just as in

ECHOS, the European population

was overweight (mean BMI 29.0 vs.

28.4 kg/m2), with a high prevalence

of sedentary lifestyle (68% vs. 70%),

type 2 diabetes (45% vs. 33%), hyper-

tension (72% vs. 74%) and CHD

(45% vs. 27%). Lifestyle modification

and statin therapy had been prescribed

to 85%. Hypertriglyceridaemia

[11.70 mmol/l (1150 mg/dl)]

occurred in 57% of men and 48% of

women not treated with a statin and

in 47% of treated men or 43% of

women. The combination of low

HDL-cholesterol and hypertriglycerid-

aemia occurred in 26% of men and

27% of women not receiving statin

treatment and in 21% of men and

25% of women receiving lipid-modi-

fying treatment.

The significance of the ECHOS

study is that most low HDL-C is

found in patients without features of

the metabolic syndrome and that the

overlap of low HDL-C with this syn-

drome is limited. Thus measuring

HDL-C only in patients with features

of the metabolic syndrome will lead to

under-treatment of this strong cardio-

vascular risk factor which is associated

with CHD. The lack of difference in

HDL-C between treated and

untreated groups confirms that statins

have little effect on HDL-C

(11,15,16). In addition ECHOS

shows that patients with low HDL-C

are over-represented in the population

with CHD. This applies especially to

ethnic minorities in European coun-

tries including Indian Asians, Arabs

and Turks and Hispanic or American

Indian populations in the USA (17) as

well as native Indian Asian popula-

tions (18). This is a group that would

benefit from multiple risk factor inter-

vention as though statins reduce their

risk in these communities still substan-

tially exceeds that of Caucasian com-

parators.

Given the high-risk associated with

low HDL-C, how should it be trea-

ted? The strategy differs given the aeti-

ology of the low HDL-C. In patients

with the metabolic syndrome, treat-

ment should be directed towards insu-

Table 1 Effects of different cardiovascular therapies on HDL-C and other features of the metabolic syndrome and endpoint trial evidence

of effects in prevention of diabetes and cardiovascular disease

Drug/treatment group

Component of the metabolic syndrome reduction (%)

DM risk reduction (%) CVD risk reduction(%)Weight/waist HDL-C TG SBP Glucose

Lifestyle (4 years) (19,20) 6–8 þ16 34 9 3 35 25–40

Aspirin (5 years) (21) 0 0 0 þ3 0 ? 25

ACE/ARB (5 years) (23,40) 0 0 0 8 0 25–32 22–26

Metformin (4 years) (19,26) 0–3 þ15 15 0–5 10 45 58

TZD (4 years) (25) þ3 þ9 12 5 8 51 10

Statin (5.5 years) (15,41,42) – 0 to þ15 15–25 0 0 0–14 20–55

Fibrate (6 years) (43,44) 0–5 þ2 to þ16 15–24 0–8 0–6 0–23 10–34

Niacin (6 years) (45) – þ10 to þ25 15–35 0 þ5 ? 22–31

Orlistat (4 years) (34) 3 þ3 1 1 4 45 ?

Sibutramine (2 years) (35) 10 þ9 25 þ4 4 ? ?

Rimonabant (2 years) (36,46,47) 6–8 þ9 to þ23 16 0–4 2–3 ? ?

ACE-I, angiotensin-I converting enzyme inhibitor; ARB, angiotensin-II type I receptor blocker; CVD, cardiovascular disease; DM, diabetes mellitus; HDL-C,

high-density lipoprotein-cholesterol; SBP, systolic blood pressure; TG, triglycerides; TZD, thiazolidinedione.

1150 EDITORIAL


lin sensitisation and weight loss while

in normoglycaemic patients then rais-

ing HDL-C directly by drug therapy

is useful. A considerable number of

approaches have been recommended

to treat low HDL-C and many have

been investigated in clinical outcome

trials (Table 1). Interventions range

form diet and lifestyle which while

enormously beneficial in prevention

ideally needs to be started early in life.

Diet and lifestyle in the Diabetes Pre-

vention Programme (19) and the Fin-

nish Diabetes Prevention Programme

(20) exert most of their effect on

reducing the future incidence of dia-

betes and little data exist in these trials

for their effects on cardiovascular

events. Aspirin prevents cardiovascular

events but there is little data on its

effect on progression to diabetes (21).

Angiotensin-I converting enzyme

inhibitors (ACE-Is) (22) and angioten-

sin II type I receptor blockers reduce

cardiovascular endpoints and also pro-

gression to diabetes (23) while thiaz-

ides and to a lesser extent beta

blockers are beneficial on cardiovascu-

lar events but both increase the inci-

dence of diabetes (24). Both

metformin and thiazolidinediones

(TZD) (glitazones; TZDs) (25)

decrease progression of impaired glu-

cose tolerance to diabetes but metfor-

min showed superior effects on CVD

in the UK-Prospective Diabetes Study

in patients with type 2 diabetes (26).

In contrast pioglitazone, the TZD

with most lipid beneficial actions in

raising HDL-C and lowering triglycer-

ides reduced cardiovascular but not

coronary endpoints but at the expense

of a deterioration in dyspnoea and

possibly cardiac failure (27).

Fibrates and nicotinic acid are well

established agents in CVD and exten-

sive data exist for their effects in mo-

notherapy on CVD. Fibrates have had

mixed trial results generally showing a

modest benefit on non-fatal events

(28) while nicotinic acid has more

obvious effects on CVD but possibly

at the expense of an increase in glu-

cose using older preparations. Nico-

tinic acid (niacin) reduces the

progression of atherosclerosis when

added to baseline statin therapy and

the results of the ARBITER – II (29)

and HDL and atherosclerosis (30)

studies are being validated in the

AIM-HIGH endpoint trial (31). The

effects of these drugs pale beside those

of statin therapy on CVD (15), but in

contrast to fibrates statins have little

effect in reducing progression to dia-

betes and microvascular complications

of diabetes. Specific HDL-C raising

drugs are in development but the cho-

lesterol ester transfer protein inhibitors

which show greatest promise by rais-

ing HDL-C by 30–70% have a differ-

ent mechanism of action to previous

HDL-C raising compounds that at

least partially work through consis-

tently shifting all particle subfraction

sizes as opposed to increasing one spe-

cies (32).

A number of weight loss strategies

and medications have been investi-

gated. The most dramatic effects on

HDL-C are seen in the morbidly

obese with bariatric surgery when gas-

troduodenal bypass surgery is

employed (33). Pharmacological

approaches in lesser degrees of obesity

[body mass index (BMI) 27–40] show

dramatic benefits in prevention of dia-

betes but sometimes (orlistat) without

obvious effects on HDL-C (34). Stud-

ies of sibutramine are less extensive

and have not addressed either diabetes

or cardiovascular endpoints (35). The

new cannabinoid receptor antagonist

rimonabant has impressive effects in

raising HDL-C (36) and an endpoint

trial – CRESCENDO (37) on its

effects in CVD with new diabetes as a

secondary endpoint is just starting.

Many of these agents are likely to

be used in combination therapy.

TZD–metformin combinations are

well established in diabetes. A combi-

nation of fenofibrate with metformin

is in the process of being licensed

while many companies are developing

fibrate-statin and nicotinic acid-statin

combinations. The first of the end-

point studies on CVD combining the

lipid neutral TZD rosiglitazone with

the ACE-I ramipril in patients with

impaired glucose tolerance (4000) and

impaired fasting glucose (1000) –

DREAM study (38) are due to be pre-

sented soon. This study will be the

first to validate combination therapy

in prevention of diabetes and it will

be interesting to observe the effects of

HDL-C seen in this population. Fur-

ther studies will have to be done in

the future to define the optimum

combination of therapies to reduce

both diabetes and CVD and many

will use HDL-C as an early surrogate

marker but it may well turn out that

different patient groups will require

different therapies. The exact choice

of agent used will depend on deter-

mining the patient’s likely benefit

from any agent as opposed to the risk

of complications. This will give the lie

to the increasingly common protocol-

based factory medicine idea of prescri-

bing all agents in all individuals in the

hope that all are sequentially additive,

when in real life marginal benefits are

seen with each addition. However this

idea should not be used as an excuse

not to control all risk factors aggres-

sively as well chosen polypharmacy

using appropriate and mutually rein-

forcing targets and medications can

have dramatic benefits on cardiovascu-

lar endpoints as was demonstrated in

the Steno-2 study in type 2 diabetes

(39) where incidentally management

of HDL-C did not form one of the

required interventions.

The field of cardiovascular medicine

is moving towards the integration of

risks of CVD and diabetes. Treatment

of cardiometabolic disease is likely to

be complex and will require consid-

erable optimisation of combination

therapies to individual risk profiles.

It should be remembered that HDL-C

is one of the principal risk factors

for CVD in all high-risk patients

and that its active management with

appropriate agents depending on the

EDITORIAL 1151


endpoint being targeted should be

a greater priority as many agents

exist that have significant benefits on

HDL-C levels.

A C K N O W L E D G E M E N T S

Dr Wierzbicki has received grant sup-

port, lecture honoraria and travel grants

from Abbott, Fournier-Solvay, Glaxo-

SmithKline, Merck kGA, Merck-Sharp

& Dohme, Pfizer, Sanofi-Aventis and

Takeda pharmaceuticals.

Anthony S. Wierzbicki

Consultant in Specialist Labora-

tory Medicine and director of

the Lipid Unit,

St. Thomas’ Hospital,

London SE 1 7EH, UK

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1152 EDITORIAL


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