HDL: who needs it?

One of the problems with writing editorials is the

capacity for events to embarrass you. Recently, I

reviewed the potential mechanisms of action and

clinical evidence base behind niacin when comment-

ing on the predictable identity of activity of one

preparation in many different patient groups (1). To

re-iterate, niacin raises HDL-C by more than other

agent and has an evidence base in surrogate outcome

studies when added to a statin and also in the origi-

nal Coronary Drug Project (CDP) outcomes study

with monotherapy (1,2). However, the capacity of

events to mis-direct commentators was shown by

the decision to abandon the AIM-HIGH trial on the

grounds of futility a few weeks later (3). There was

no observable benefit of niacin and indeed a sugges-

tion of an increased rate of strokes.

Surrogate outcome studies have a potential to mis-

lead based on the performance or stability of the

marker studied (4). Thus, regulators have tended to

rely even more on outcome studies. This has been

noticeable when surrogate markers such a glucose

(or microvascular events) have misled clinicians in

appraising classes of drugs such as thiazolidionedi-

ones when assessed on their overall outcomes of

CVD events. Whether other new classes of hypogly-

caemic drugs [e.g. Di-peptidyl peptidase (DPP)-IV

inhibitors, novel insulins, glucagon-like peptide

(GLP)-1 analogues] show similar effects is unclear,

but under study. It is notable that these studies are

not powered for non-inferiority, but for superiority

over conventional treatments although this may be

unlikely given the previous results of the UK Pro-

spective Diabetes Study (UKPDS) (5).

The Atherothrombosis Intervention in Metabolic

syndrome with low HDL ⁄ high triglycerides: Impact

on Global Health outcomes (AIM-HIGH) trial was

designed to test the additive effects of niacin on

HDL-C in a dyslipidaemic secondary prevention

population that would be maintained at optimum

target LDL-C in both groups (6). It actually recruited

a dyslipidaemic population with a HDL-C of

0.90 mmol ⁄ l, an atherogenic index (TG:HDL-C

ratio) of 2 and LDL-C 1.84 mmol ⁄ l (7). The study

was powered for a 25% difference in CVD events (6)

based on the outcomes of the Veterans Affairs HDL

Intervention (VA-HIT) trial using gemfibrozil – a

fibrate (8). This suggested that 3500 patients would

be required and 3414 were recruited.

However, a simple reading of the trial might well

be misleading. The rate of events will be progres-

sively reduced as LDL-C in parallel with absolute

reductions in LDL-C. As trial designs are based on

historical rates of CVD events, it has been increas-

ingly common for trials [e.g. Study of the Effective-

ness of Additional Reduction in Cholesterol and

Homocysteine (SEARCH), Improved Reduction of

Outcomes: VYTORIN Efficacy International Trial

(IMPROVE-IT)] to be extended or have their num-

bers increased. Although the trial results have not

been published, the event rate at 1% was low for this

population. In addition, adjustment of LDL-C levels

to < 70 mg ⁄ dl (< 1.75 mmol ⁄ l) was allowed using

either statin or ezetimibe in both groups leaving this

as an HDL-C adjustment trial. However, niacin has

protean actions on all lipid fractions (1), and so this

design would underestimate its likely effects. In addi-

tion, in all trials drop-out rates vary from 10% to

20% and might be higher with niacin given the

continuing high rate of flushing with modified-

release preparations (e.g. Niaspan used in AIM-

HIGH). Although far less than those found with

crystalline niacin in CDP, expectations of side-effects

have changed dramatically over the last 40 years. In

the active run-in to AIM-HIGH, more women

(39%) discontinued than men (18%) mostly because

of flushing. Thus, again the expectations of the trial

were high if side-effects resulted in higher rates of

discontinuation in the active treatment arm even

though the ‘placebo’ group received a 50 mg flush-

ing-induction dose to maintain blinding (6).

The history of end-point trials with second-line

agents is also a potential factor in explaining these

results. The fibrate trials offer some potential analo-

gies. The Fenofibrate Intervention in Endpoint Low-

ering in Diabetes (FIELD) study (9) although

showing a small to moderate effect was confounded

by statin drop-in that occurred more often in higher

risk patients (10) and in those not receiving fenofi-

brate, which can reduce LDL-C by 6%. In AIM-

HIGH, the likeliest potential confounder will be

found in differential prescribing of ezetimibe – in

itself a controversial additional agent. Recently, the

combination of simvastatin and ezetimibe has been

shown to reduce CVD events by 23% in the Study

of Heart and Renal Protection (SHARP) trial in

patients with chronic renal failure (n = 9500) (11),

whereas in the previous smaller Simvastatin-Ezetim-

ibe in Aortic Stenosis (SEAS) trial (n = 1800) in

patients with aortic stenosis (12), this combination

only reduced CVD events by 17%, which was not

EDITORIAL

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1111–1114 1111

HDL

metabolism is

more complex

than that of

LDL

significant, but was probably confounded by the

complex pathophysiology of aortic stenosis (13).

Another hint is offered by the Action to Control

Cardiovascular Risk in Diabetes (ACCORD) trial,

where fenofibrate was added to baseline simvastatin

in patients with type 2 diabetes (14). Again, the fi-

brate reduced CVD events only by a non-significant

7% in a population with a wide recruitment range of

HDL and triglyceride levels (< 6 mmol ⁄ l), but actu-

ally recruited patients with rather unremarkable lev-

els (HDL-C 1.05 mmol ⁄ l; triglycerides 1.7 mmol ⁄ l).

Only in a pre-specified population with low HDL-C

(< 0.85 mmol ⁄ l) and raised triglycerides (> 2.3 mmol ⁄ l)was a significant 22% reduction in CVD events seen

(p = 0.06) in the univariate analysis, and not in the

multivariate heterogeneity analysis. A small effect of

added fibrate on baseline statin therapy has also been

seen in a responder sub-group from a retrospective

observational study of patients with a high athero-

genic index (TG:HDL ratio) treated with fibrate-sta-

tin combination therapy (15). In AIM-HIGH, only a

few patients are likely to have an atherogenic index

(TG: HDL-C ratio) > 3.5, and these may actually

show a benefit as has been seen in the fibrate trials

(10). This suggests that HDL (and triglyceride) inter-

ventions that work primarily by changing HDL (and

LDL) particle sizes may only be beneficial in patients

with high atherogenic indices. This group has not

been systematically studied in any surrogate or event

outcome studies.

The profoundly different design of the Heart Pro-

tection-2 Treatment of HDL to Reduce the Incidence

of Vascular Events (HPS2-THRIVE) trial may give a

different result (16). The form of niacin being used

is different, as it is combined with a flush inhibitor

(laropiprant) that offers benefits in lower rates of

flushing and discontinuation. The study is far larger

comprising 30,000 patients, but no prior lipid quali-

fication criteria. It includes 6000 patients with diabe-

tes. Given the larger size of the trial, its longer

follow-up and more rigorous design to exclude dif-

ferential additional LDL-C reduction it is far likelier

to give a definitive answer as to the added benefits of

niacin on top of statin therapy.

High density lipoprotein is well established from

epidemiological studies as having protective effects

from atherosclerotic disease (17). This is mediated

by multiple mechanisms, and HDL metabolism is far

more complex than that of LDL-C. Recently, atten-

tion has begun to change from measurements of

HDL-C concentrations to measures of the functional

capacity of HDL to mediate reverse cholesterol trans-

port (18). This has occurred, as it has been noted

that low HDL-C may actually indicate high HDL

turnover and hyper-functional particles. ApoA-1

Milano is associated with low plasma HDL-C, but

marked decreases in coronary atheroma burden in

human intervention studies (19). Reconstituted HDL

infusions had similar, but lesser effects; however,

none of the studies were completely powered, given

similar numbers and short follow-up times as used

in the ApoA-1 Milano studies. High HDL levels in

patients with CETP deficiency may also not be pro-

tective in migration studies. Whether HDL-reverse

cholesterol transport is the most appropriate action

of HDL to study or develop is unknown, although a

strong alternative case can be made for anti-inflam-

matory actions, given the critical role of inflamma-

tion in CVD and especially in plaque destabilisation

and acute coronary syndromes.

The other class of HDL raising drugs is the choles-

terol ester transfer protein (CETP) inhibitors. While

undoubtedly effective in raising HDL-C levels, these

agents have a profoundly different mechanism of

action to fibrates or niacin. Early studies have also

shown little effect on short-term surrogate markers

such as endothelial function. The only outcome

study to date with a CETP inhibitor [Investigation

of Lipid Level Management to Understand Its

Impact in Atherosclerotic Events (ILLUMINATE)

trial using torcetrapib] was terminated prematurely

on the grounds of excess CVD events that were

ascribed to the hypertensive and aldosterone-raising

effects that were specific to the compound (19,20).

Other compounds in the class do not show similar

effects. No CETP inhibitor to date has shown an

increase in biliary cholesterol efflux, but all reduce

LDL-C in proportion to their efficacy in raising

HDL-C. To date, virtually all forms of LDL-C reduc-

tion including surgical interventions (e.g. POSCH)

have been shown to reduce CVD events (21). The

potential thus remains for CETP inhibitors to show

benefits in CVD event reduction, but only as a result

of their smaller, but still significant action in reduc-

ing LDL-C.

The problem with HDL is that no one really

understands it. Cheap traditional plasma measures of

HDL may not be appropriate for this primarily intra-

cellular multiply recycled particle. However, if CETP

inhibitors do work through LDL-C reduction in out-

come studies, it will not be the first time a flawed

initial hypothesis has led to a useful outcome prod-

uct. The AIM-HIGH trial reminds us of the need to

design simple protocols and to build efficacy safety

margins into trials despite what the power calcula-

tions say. We know far less than we think. The Food

and Drugs Administration in the USA while review-

ing the place of fibrates has now formally requested

that a CVD outcomes trial is conducted in patients

with a high atherogenic index (22).

1112 Editorials

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1111–1114

Disclosure

None.

Anthony S. WierzbickiDepartment of Metabolic Medicine ⁄ Chemical Pathology,

Guy’s & St Thomas’ NHS Trust, St Thomas Hospital,London, UK

Email: Anthony.Wierzbicki@kcl.ac.uk

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term fenofibrate therapy on cardiovascular events

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ED ITORIAL

The Polypill – multiple drug combinations are not theanswer

It is an interesting concept – combine multiple risk-

reducing drugs in one tablet and save the world. In

this way drugs are placed ahead of lifestyle changes

(which have often failed) and as a single pill adher-

ence to medication is projected to increase and cost

decrease. This sounds too good to be true and it

almost certainly is.

The combination proposed includes an angiotensin

converting enzyme (ACE) inhibitor, statin, thiazide

diuretic, beta blocker and aspirin, and the target

individuals are those with established vascular disease

(often referred to as secondary prevention) and those

without known vascular disease but who, as a result

of multiple risk factors, are at high risk (e.g. smok-

ers, hypertensives, diabetics, hyperlipidaemics) – so-

called primary prevention.

As a concept maximising risk reduction with

minimal inconvenience to the patient is everyone’s

therapeutic goal. The problem with the Polypill as

proposed is first that it mixes drugs that titrate to

maximal effect with those with a flat dose–response

curve. Titration of ACE inhibitor, statin and beta

Editorials 1113

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, November 2011, 65, 11, 1111–1114