Intervening on HDL-C: Is it possible? Does it work?

References1 Zimmet P, Alberti KG, Shaw J. Global and societal implications of

the diabetes epidemic. Nature 2001; 414: 782–7.

2 Yusuf S, Ounpuu S, Anand S. The global epidemic of atheroscle-

rotic cardiovascular disease. Med Princ Pract 2002; 11 (Suppl. 2):

3–8.

3 Anderson KM, Odell PM, Wilson PW et al. Cardiovascular disease

risk profiles. Am Heart J 1991; 121 (1 part 2): 293–8.

4 Assmann G, Schulte H. Relation of high-density lipoprotein cho-

lesterol and triglycerides to incidence of atherosclerotic coronary

artery disease (the PROCAM experience). Prospective Cardiovascu-

lar Munster study. Am J Cardiol 1992; 70: 733–7.

5 Sarwar N, Danesh J, Eiriksdottir G et al. Triglycerides and the risk

of coronary heart disease: 10,158 incident cases among 262,525

participants in 29 Western prospective studies. Circulation 2007;

115: 450–8.

6 Walldius G, Jungner I, Holme I et al. High apolipoprotein B, low

apolipoprotein A-I, and improvement in the prediction of fatal

myocardial infarction (AMORIS study): a prospective study. Lancet

2001; 358: 2026–33.

7 Ingelsson E, Schaefer EJ, Contois JH et al. Clinical utility of differ-

ent measures for prediction of coronary heart disease in men and

women. JAMA 2007; 298: 776–85.

8 Austin MA. Triglyceride, small, dense low-density lipoprotein, and

the atherogenic lipoprotein phenotype. Curr Atheroscler Rep 2000;

2: 200–7.

9 Lemieux I, Pascot A, Couillard C et al. Hypertriglyceridemic waist:

a marker of the atherogenic metabolic triad (hyperinsulinemia;

hyperapolipoprotein B; small, dense LDL) in men? Circulation

2000; 102: 179–84.

10 Rizzo M, Berneis K. Who needs to care about small, dense low

density lipoproteins? Int J Clin Pract 2007; 61: 1949–56.

11 St-Pierre AC, Cantin B, Dagenais GR et al. Low-density lipopro-

tein subfractions and the long-term risk of ischemic heart disease

in men: 13-year follow-up data from the Quebec Cardiovascular

Study. Arterioscler Thromb Vasc Biol 2005; 25: 553–9.

12 Ensign W, Hill N, Heward CB. Disparate LDL phenotypic classifi-

cation among 4 different methods assessing LDL particle character-

istics. Clin Chem 2006; 52: 1722–7.

13 Hirano T, Ito Y, Saegusa H et al. A novel and simple method

for quantification of small, dense LDL. J Lipid Res 2003; 44:

2193–201.

14 Otvos JD, Collins D, Freedman DS et al. Low-density lipoprotein

and high-density lipoprotein particle subclasses predict coronary

events and are favorably changed by gemfibrozil therapy in the

Veterans Affairs High-Density Lipoprotein Intervention Trial.

Circulation 2006; 113: 1556–63.

15 Wilson PWF, Myers GL, Cooper GR, Grundy SM, Labarthe DR.

Lipoprotein subclasses and particle size and CVD risk. In: Myers

GL, Christenson RH, Cushman M, Ballantyne CM, Cooper GR,

Grundy SM, Labarthe DR, Levy D, Rifai N, Wilson PWF, eds. The

National Academy of Clinical Biochemistry Laboratory Medicine

Practice Guidelines: Emerging Biomarkers of Cardiovascular Disease

and Stroke. Washington, DC, USA: American Association for Clin-

ical Chemistry, 2006: 42–6.

16 Ulrich J, Dittrich M, Pietzsch J. Factors influencing the formation

of small dense LDL particles in dependence on the presence of the

metabolic syndrome and on the degree of glucose intolerance. Int

J Clin Pract 2007; 61: 1798–804.

17 Gardner CD, Fortmann SP, Krauss RM. Association of small low-

density lipoprotein particles with the incidence of coronary artery

disease in men and women. JAMA 1996; 276: 875–81.

18 Hokanson JE. Hypertriglyceridemia and risk of coronary heart dis-

ease. Curr Cardiol Rep 2002; 4: 488–93.

19 National Cholesterol Education Program (NCEP). Executive Sum-

mary of the Third Report of the National Cholesterol Education

Program (NCEP) Expert Panel on Detection, Evaluation, and

Treatment of High Blood Cholesterol in Adults (Adult Treatment

Panel III). JAMA 2001; 285: 2486–97.

20 Campos H, Perlov D, Khoo C et al. Distinct patterns of lipopro-

teins with apoB defined by presence of apoE or apoC-III in

hypercholesterolemia and hypertriglyceridemia. J Lipid Res 2001;

42: 1239–49.

21 Sacks FM, Alaupovic P, Moye LA et al. VLDL, apolipoproteins

B, CIII, and E, and risk of recurrent coronary events in the

Cholesterol and Recurrent Events (CARE) trial. Circulation 2000;

102: 1886–92.

22 Frost RJ, Otto C, Geiss HC et al. Effects of atorvastatin versus

fenofibrate on lipoprotein profiles, low-density lipoprotein subfrac-

tion distribution, and hemorrheologic parameters in type 2 diabe-

tes mellitus with mixed hyperlipoproteinemia. Am J Cardiol 2001;

87: 44–8.

23 Wierzbicki AS. FIELDS of dreams, fields of tears: a perspective on

the fibrate trials. Int J Clin Pract 2006; 60: 442–9.

24 Staels B, Dallongeville J, Auwerx J et al. Mechanism of action of

fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98:

2088–93.

doi: 10.1111/j.1742-1241.2007.01570.x

ED ITORIAL

Intervening on HDL-C: Is it possible? Does it work?*

High-density lipoprotein (HDL) cholesterol is

acknowledged to be a major cardiovascular risk fac-

tor in epidemiological studies in humans as the

review by Bruckert and Hansen in this issue demon-

strates (1). A number of questions have bedevilled

the field of HDL metabolism. Are all HDL particles

equally effective in cardiovascular prevention? Is all

HDL functional? Which particles are the most active?

Can different HDL species be differentiated? Is phar-

maceutical intervention to raise HDL-C feasible or

effective?

High-density lipoprotein particles vary more than

low-density lipoprotein (LDL) particles in their

In terms of

chronic HDL-

raising therapy

the best estab-

lished drug is

niacin

*As cardiovascular disease prevention and metabolic diseases

section editor for the Journal, Anthony S. Wierzbicki withdrew

from the review process and deferred all editorial decisions to

Graham Jackson.

1782 Editorials

ª 2007 The AuthorsJournal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, November 2007, 61, 11, 1779–1790

composition with regard to apolipoproteins. Thus

though apolipoprotein (apo) A-1 is present in all

particles 30% of HDL contains apolipoprotein A-2

as well as varying quantities of multiple other apo-

lipoproteins (all up to apoM except for apoB).

Recent proteomic studies of HDL particles have

shown that they contain 60 protein species (2) as

opposed to the mere 12 found associated with LDL

(3). Thus the potential for heterogeneity in HDL is

far greater than HDL and different particles may

have differential effects with regard to the pleiotro-

pic actions of HDL in reverse cholesterol transport,

coagulation, inflammation and apoptosis. Simply in

the field of reverse cholesterol transport it has

become obvious that different particles behave dif-

ferently. Thus apoM stabilises HDL discs but that

once cholesterol and its esters start being added to

HDL by the action of the ABC-A1 transporter it

dissociates and is recycled (4). As the HDL particles

increase in size (HDL-3 to HDL-2 by density), cho-

lesterol loading switches to the ABC-G1 pathway.

In patients with cholesterol ester transfer protein

deficiency ultra-large light HDL particles (of LDL

density) are seen and variable results have been

obtained when investigating their efficacy in reverse

cholesterol transport.

While many studies show that lowering LDL-C is

both possible and effective in terms of reducing car-

diovascular events the same cannot be said as yet for

HDL-C. Numerous drugs have been developed to

raise HDL-C (5) and many agents raise HDL-C as

part of their action (6). Proof for the concept that

raising HDL-C would affect rates of atherosclerosis

was provided by the intravascular ultrasound study

(IVUS) of the effects of weekly infusions of a hyper-

functional apolipoprotein A-1- (apoA-1) Milano (7).

However recombinant HDL (rHDL) in 183 patients

with established coronary heart disease with an LDL-

C of 2.11 mmol/l using a similar infusion protocol in

the Effect of Reconstituted high-density lipoprotein

on Atherosclerosis- Safety and Efficacy (ERASE) trial

showed borderline benefit (3.41 vs. 1.62%;

p ¼ 0.07) on inter-group IVUS analysis indicating

either a different protocol or different doses were

required (8).

In terms of chronic HDL-raising therapy the best

established drug is niacin (nicotinic acid). However,

its actions are pleiotropic and include effects on tri-

glycerides, LDL-C and lipoprotein (a) as well as

HDL-C though it is currently the most effective

HDL raising agent (20–25%). Niacin has been shown

to reduce progression of carotid intima media-thick-

ness (cIMT) when added to either statin (9) or coles-

tipol (10) and also reduces progression of coronary

atherosclerosis when combined with a fibrate and a

bile acid sequestrant (11). In monotherapy niacin

reduced events in the Coronary Drug Project by 22%

at 5 years and total mortality by 18% in a 15-year

post hoc analysis (12). Combination therapy studies

adding niacin to optimal statin therapy are underway

– AIM-HIGH and Treatment of High density lipo-

protein to Reduce the Incidence of Vascular

Events(THRIVE /Heart Protection Study 3) – to

evaluate its effects on cardiovascular end-points.

Fibrates are also pleiotropic agents. They are either

peroxisomal proliferator activating receptor alpha

(PPAR-a) agonists (e.g. fenofibrate) or possibly pan-

PPAR agonists (bezafibrate) and all except gemfibro-

zil induce apolipoprotein A-1 production. They raise

HDL-C by 5–15%. They also affect triglyceride

metabolism through actions on apoC-III and lipo-

protein lipase and affect up to 300 genes as they are

nuclear signal analogues (13). Some, e.g. fenofibrate

and LY518674, also reduce LDL-C probably by acting

through preprotein convertase subtilisin kexin-9

(PCSK-9). Fibrates have been shown to reduce pro-

gression of cIMT and also mean lumen diameter in

quantitative coronary angiography studies (14). In

clinical end-point studies results have been more

ambiguous (15). Fibrates showed benefits with the

gemfibrozil trials in a general population and in sec-

ondary prevention with low HDL-C (15). However,

in the Fenofibrate Intervention in Endpoint Lowering

in Diabetes (FIELD) study fenofibrate reduced car-

diovascular events in some unexpected groups in a

very confusing study showing little benefit on HDL-

C (15,16). The combination of fibrates, niacin and

cholestyramine has been shown to reduce cIMT pro-

gression in the Air Force Regression study (AFREGS)

(11).

Thiazolidinediones (glitazones) are peroxisomal

proliferator activating receptor-gamma (PPAR-c)

agonists. Their principal action is to reduce blood

glucose by increasing tissue insulin sensitivity but

pioglitazone in contrast to rosiglitazone raises HDL-

C by 10% and there has been speculation that like

many PPAR agonists it shows selectivity not specific-

ity – in this case an additional significant PPAR-aaction with consequent multiple actions on HDL

and triglyceride metabolism. In the Carotid Intimal-

Medial THICkness in Atherosclerosis using pioGlit-

azOne (CHICAGO) study pioglitazone reduced the

progression of cIMT (17). Again end-point trials are

confusing. In a secondary prevention population

pioglitazone reduced total cardiovascular events by

14% (p ¼ 0.09) and cardiovascular events exclud-

ing procedures by 16% (p ¼ 0.04) (18). However,

these beneficial effects were counterbalanced by an

increase in cardiac failure probably secondary to

PPAR-c induced aldosterone activation and fluid

Editorials 1783


retention (19). A recent meta-analysis of data with

rosiglitazone that has fewer beneficial effects on lipid

profile and indeed raises LDL-C suggests that this

drug may be associated with a 43% increased rate of

cardiovascular events (20).

Orexigenic (weight-loss) drugs can also raise

HDL-C and reduce triglycerides with effects parallel-

ing those imputed from the Framingham study

where a 1-kg weight loss reduced triglycerides by

2%, blood pressure by 2/1.5 mmHg, and raised

HDL-C by 2% paralleled by a 1-cm reduction in

waist circumference. These findings, blood pressure

apart, have been reproduced in trials with orlistat, si-

butramine and rimonabant. Yet there are no pro-

spective randomised control trial studies of the

effects of weight loss induced on rate of progression

of cIMT or cardiovascular events, though trials on

cardiovascular events with sibutramine and rimona-

bant are underway (21).

However, none of the current HDL-C raising

agents increase levels by more than 25% (22). Ani-

mal studies suggested that inhibition of CETP

would reduce progression of atherosclerosis. Data

on the relationship between CETP deficiency and

coronary events in man were more controversial

(23). Torcetrapib raised HDL-C levels by 70%,

though early studies did not show the characteristic

rise in faecal sterol excretion seen with other lipid-

lowering therapies. The results were sufficiently

encouraging for both surrogate marker and

end-point studies to be commenced. In the Rating

Atherosclerotic Disease by Imaging with A New

CETP Inhibitor (RADIANCE 1) study of torcetrapib

on cIMT in 850 patients with familial hypercho-

lesterolaemia on top of 56.5 mg atorvastatin the

drug raised HDL-C by 51.9% and reduced LDL-C

by 20.6%, yet cIMT increased by a nonsignificant

0.0047 mm/year on inter-group comparison (Fig-

ure 1) (24). Results of the RADIANCE 2 study in

2918 patients with mixed hyperlipidaemia (triglyce-

rides 1.75–5.65 mmol/l) on a baseline of 13.5 mg

atorvastatin were similar as torcetrapib therapy

raised HDL-C by 63.4 % and reduced LDL-C by

17.7% but again cIMT increased by 0.0049 mm/

year. The coronary surrogate marker studies were

also disappointing. In the Investigation of Lipid

Level management Using coronary ultraSound To

assess Reduction of Atherosclerosis by CETP inhibi-

tion and HDL Elevation (ILLUSTRATE) trial using

intravascular ultrasound torcetrapib raised HDL-C0.4

LIPID

ARBITER-2

PLAC-2

MARS

REGRESSKAPS

B KAPSCAIVS

FHC

AKAPSMETROR

RADIANCE-1

CLAS

R2 = 0.20

ASAP

0.35

0.3

Fra

ctio

nal

ch

ang

e in

CC

A IM

T (

ISD

un

it/y

r)

0.2

0.15

0.25

0.1

0.05

00 10 20 30

Change in LDL-C & HDL-C (%)40 50 60 70 80

Figure 1 Relationship of change in common carotid artery

intima media thickness with overall relative change in lipid

subfractions in randomised trials. ACAP, Asymptomatic

Carotid Artery Progression; ASAP, Atorvastatin Simvastatin

Atherosclerosis Progression; BCAP, Beta-blocker

Cholesterol Asymptomatic Plaque; CAIUS, Carotid

Atherosclerosis Italian Ultrasound Study; CLAS, Cholesterol

Lowering Atherosclerosis Study; FHC, Familial

HyperCholesterolaemia trial; KAPS, Kuopio Atherosclerosis

Prevention Study; LIPID, Long-Term Intervention with

Pravastatin in Ischemic Disease; MARS, Monitored

Atherosclerosis Regression Study; METEOR, Measuring

Effects on intima media Thickness: an Evaluation Of

Rosuvastatin; PLAC-2, Pravastatin Lipids And

Atherosclerosis in the Carotid Arteries-2; RADIANCE,

Rating Atherosclerotic Disease by Imaging with A New

CETP Inhibitor; REGRESS, Regression Growth Evaluation

Study

2A-Plus Px

CAMELOT

REVERSAL-P

REVERSAL-A

ACTIVATE

ASTEROID

R2 = 0.30

A-Plus

ILLUSTRATE-P ILLUSTRATE-Px

Ch

ang

e in

ath

ero

ma

volu

me

(%)

1.5

1

0.5

–0.5

00 10–10 20 30

Change in LDL-C & HDL-C (%)

40 50 60 70 80

Figure 2 Relationship of change in coronary artery

intravascular ultrasound measured atheroma volume with

overall relative change in lipid subfractions in randomised

trials. A-Plus, Avasimibe and Progression of Lesions on

UltraSound; ACTIVATE, ACAT Intravascular

Atherosclerosis Treatment Evaluation; CAMELOT,

Comparison of Amlodipine vs. Enalapril to Limit

Occurrences of Thrombosis; ILLUSTRATE, IVUS Study to

Compare Torcetrapib/Atorvastatin to Atorvastatin Alone in

Subjects With Coronary Heart Disease – Placebo (P) or

Torcetrapib therapy (Px); REVERSAL, Reversal of

Atherosclerosis with Aggressive Lipid Lowering –Pravastatin

40 mg (P) or Atorvastatin 80 mg (A)

When torcetra-

pib therapy is

plotted by sum

of lipid

changes the

results of

RADIANCE and

ILLUSTRATE are

entirely

predictable

1784 Editorials


by 61% and reduced LDL-C by 20% but had no

significant effect on atheroma volume (Figure 2)

(25). It was notable in this 2 year study of 1188

patients that torcetrapib therapy was associated as

usual with hypertensive changes (4.6/2.0 mmHg)

and 6% of patients having a blood pressure rise of

>15 mmHg. An increase was seen in rates of acute

coronary syndromes (8.0% vs. 5.7%) and revascu-

larisation (19.3% vs. 15.9%), suggesting that torcet-

rapib may be having adverse effects on plaque

stability. While these trials were underway the par-

allel Investigation of Lipid Level management to

Understand its IMpact in ATherosclerotic Events

(ILLUMINATE) study of 15,000 secondary preven-

tion patients was discontinued after 1 year due to a

30% excess of cardiovascular deaths (82 vs. 51) in

the torcetrapib arm.

It would be nice to combine the data from inter-

vention trials with all these agents onto simple

graphs. Unfortunately this is more difficult than it

seems. While it is possible to combine trials using

end-points and quantitative coronary angiography

(QCA) mean lumen diameter as end-points giving a

linear relationship between change in mena lumen

diameter and extent of lipid changes (26) this is not

so easy for cIMT. Most information should be avail-

able from cIMT studies but unfortunately these stud-

ies differ in the end-points chosen – thus varying

between mean and maximum measurements, single

section/artery or averages of up to 12 segments and

separate data for a common end-point, e.g. distal

common carotid artery IMT is often not provided in

the published data (27). The only way to combine

the studies is by assuming that relative changes are

constant compared to variances (28). This approach

has been used to validate the effect of changes in

cIMT with diet therapies and cardiovascular events

(28). The heterogeneity of the effects on lipid profiles

in the lipid lowering trials means that studies have to

be interpreted using the combined relative change in

HDL-C and LDL-C. Pure changes in HDL-C in these

trials are not informative as they are usually out-

weighed by the effects on LDL-C but the results can-

not be explained as being due to the LDL-lowering

effects of any of these agents alone. The relationship

between cIMT and changes in lipid profiles in the

trials is complex and indicates either limitations in

the methodology or possibly combined luminal and

intimal remodelling occurring with extreme changes

in lipids (Figure 1). However, IVUS studies have

been performed by common protocols and methods,

yet the relationship for absolute changes is reason-

ably simple but with high variance in the placebo

groups (Figure 2). When torcetrapib therapy is plot-

ted by sum of lipid changes the results of RADI-

ANCE and ILLUSTRATE are entirely predictable in

the context of other trials – minimal change (Fig-

ures 1 and 2). The data for common carotid artery

IMT are similar for torcetrapib and the Cholesterol

Lowering Atherosclerosis Study (CLAS) using a com-

bination of niacin and colestipol (29). Therefore,

CETP inhibition may induce intimal remodelling but

the question remains as to whether the excess mor-

tality is drug-specific or general to the mechanism of

action. In some ways this debate is analogous to that

which occurred for PPAR-c agonists. Troglitazone

did reduce progression to diabetes (as later did rosig-

litazone) but caused fulminant liver failure; in con-

trast, other PPAR-c agonists have no effect or

beneficial effects on liver function (transaminases)

and hepatic steatosis (30). Thus only when biomar-

kers of poor prognosis in ILLUMINATE are identi-

fied and the effects of other CETP inhibitors are

investigated will it become clear whether this drug

class has promise or fundamental problems.

Epidemiological and basic science evidence sup-

ports the critical role of HDL in the prevention of

atherosclerosis. Some drugs that raise HDL-C mod-

erately, e.g. niacin, have already proved their role in

clinical trials but remain limited by side effects.

Intervening to raise HDL therapeutically by 25–50%

remains a dream. The disappointing and confusing

results of the torcetrapib trials hopefully will not

stunt research into methods of raising HDL-C by as

much as statins lower LDL-C.

Disclosure

Dr Wierzbicki has received grant support, lecture

honoraria and travel grants from Abbott, Fournier-

Solvay, GlaxoSmithKline, Merck kGA, Merck-Sharp

& Dohme, Pfizer, sanofi-aventis and Takeda Pharma-

ceutical.

A. S. WierzbickiSt Thomas Hospital,

London, UKEmail: [email protected]

References1 Bruckert E, Hansen BJ. HDL-c is a powerful predictor of cardio-

vascular events. Int J Clin Pract 2007; 61: 1905–13.

2 Vaisar T, Pennathur S, Green PS et al. Shotgun proteomics

implicates protease inhibition and complement activation in the anti-

inflammatory properties of HDL. J Clin Invest 2007; 117: 746–56.

3 Karlsson H, Leanderson P, Tagesson C et al. Lipoproteomics I:

mapping of proteins in low-density lipoprotein using two-dimen-

sional gel electrophoresis and mass spectrometry. Proteomics 2005;

5: 551–65.

4 Wolfrum C, Poy MN, Stoffel M. Apolipoprotein M is required for

prebeta-HDL formation and cholesterol efflux to HDL and pro-

tects against atherosclerosis. Nat Med 2005; 11: 418–22.

5 Wierzbicki AS. Lipid-altering agents: the future. Int J Clin Pract

2004; 58: 1063–72.

Editorials 1785


6 Wierzbicki AS. Low HDL-cholesterol: common and under-treated,

but which drug to use? Int J Clin Pract 2006; 60: 1149–53.

7 Nissen SE, Tsunoda T, Tuzcu EM et al. Effect of recombinant

ApoA-I Milano on coronary atherosclerosis in patients with acute

coronary syndromes: a randomized controlled trial. JAMA 2003;

290: 2292–300.

8 Tardif JC, Gregoire J, L’Allier PL et al. Effects of reconstituted

high-density lipoprotein infusions on coronary atherosclerosis: a

randomized controlled trial. JAMA 2007; 297: 1675–82.

9 Taylor AJ, Sullenberger LE, Lee HJ et al. Arterial Biology for the

Investigation of the Treatment Effects of Reducing Cholesterol

(ARBITER) 2: a double-blind, placebo-controlled study of

extended-release niacin on atherosclerosis progression in secondary

prevention patients treated with statins. Circulation 2004; 110:

3512–7.

10 Blankenhorn DH, Azen SP, Kramsch DM et al. Coronary angio-

graphic changes with lovastatin therapy. The Monitored Athero-

sclerosis Regression Study (MARS). Ann Intern Med 1993; 119:

969–76.

11 Whitney EJ, Krasuski RA, Personius BE et al. A randomized trial

of a strategy for increasing high-density lipoprotein cholesterol lev-

els: effects on progression of coronary heart disease and clinical

events. Ann Intern Med 2005; 142: 95–104.

12 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: 1245–55.

13 Chapman MJ. Fibrates in 2003: therapeutic action in atherogenic

dyslipidaemia and future perspectives. Atherosclerosis 2003; 171:

1–13.

14 Effect of fenofibrate on progression of coronary-artery disease in

type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a

randomised study. Lancet 2001; 357: 905–10.

15 Wierzbicki AS. FIELDS of dreams, fields of tears: a perspective on

the fibrate trials. Int J Clin Pract 2006; 60: 442–9.

16 Keech A, Simes RJ, Barter P et al. Effects of long-term fenofibrate

therapy on cardiovascular events in 9795 people with type 2 diabe-

tes mellitus (the FIELD study): randomised controlled trial. Lancet

2005; 366: 1849–61.

17 Mazzone T, Meyer PM, Feinstein SB et al. Effect of pioglitazone

compared with glimepiride on carotid intima-media thickness in

type 2 diabetes: a randomized trial. JAMA 2006; 296: 2572–81.

18 Dormandy JA, Charbonnel B, Eckland DJ et al. Secondary preven-

tion of macrovascular events in patients with type 2 diabetes in

the PROactive Study (PROspective pioglitAzone Clinical Trial In

macroVascular Events): a randomised controlled trial. Lancet 2005;

366: 1279–89.

19 Yki-Jarvinen H. The PROactive study: some answers, many ques-

tions. Lancet 2005; 366: 1241–2.

20 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocar-

dial infarction and death from cardiovascular causes. N Engl J Med

2007; 356: 2457–71.

21 Wierzbicki AS. Primary and secondary prevention in obesity. Int J

Clin Pract 2007; 61: 1431–4.

22 Chapman MJ, Assmann G, Fruchart JC et al. Raising high-den-

sity lipoprotein cholesterol with reduction of cardiovascular risk:

the role of nicotinic acid–a position paper developed by the

European Consensus Panel on HDL-C. Curr Med Res Opin 2004;

20: 1253–68.

23 Forrester JS, Makkar R, Shah PK. Increasing high-density lipo-

protein cholesterol in dyslipidemia by cholesteryl ester transfer

protein inhibition: an update for clinicians. Circulation 2005;

111: 1847–54.

24 Kastelein JJ, van Leuven SI, Burgess L et al. Effect of torcetrapib

on carotid atherosclerosis in familial hypercholesterolemia. N Engl

J Med 2007; 356: 1620–30.

25 Nissen SE, Tardif JC, Nicholls SJ et al. Effect of torcetrapib on the

progression of coronary atherosclerosis. N Engl J Med 2007; 356:

1304–16.

26 Wierzbicki AS. Lipid-altering therapies and the progression of ath-

erosclerotic disease. Cardiovasc Intervent Radiol 2007; 30: 155–60.

27 Bots ML. Carotid intima-media thickness as a surrogate marker

for cardiovascular disease in intervention studies. Curr Med Res

Opin 2006; 22: 2181–90.

28 Lorenz MW, Markus HS, Bots ML et al. Prediction of clinical car-

diovascular events with carotid intima-media thickness: a system-

atic review and meta-analysis. Circulation 2007; 115: 459–67.

29 Blankenhorn DH, Selzer RH, Crawford DW et al. Beneficial effects

of colestipol-niacin therapy on the common carotid artery. Two-

and four-year reduction of intima-media thickness measured by

ultrasound. Circulation 1993; 88: 20–8.

30 Stumvoll M, Haring HU. Glitazones: clinical effects and molecular

mechanisms. Ann Med 2002; 34: 217–24.

doi: 10.1111/j.1742-1241.2007.01535.x

ED ITORIAL

Learning lessons from REACH

The Reduction of Atherothrombosis for Continued

Health (REACH) registry (1,2) provides valuable

data regarding the risks of future atherothrombotic

events in high-risk patients treated in a ‘real world’

setting, i.e. in primary care and as outpatients, rather

than as inpatients. These data can be used to provide

feedback to physicians and healthcare organisations

regarding the level of care currently provided and

the potential areas for improvement.

Practice care guidelines are developed based on

the evidence base, which primarily consists of

randomised controlled trials (RCTs). However,

RCTs are often conducted in hospital settings with

strictly controlled medication regimens; this does

not reflect the conditions in which most patients

are treated. The REACH registry has highlighted

that there is a substantial gap between guideline

recommendations and actual clinical practice in the

care of patients with or at risk for atherothrombo-

sis (2). Established medical therapies are underuti-

lised throughout all geographic regions studied,

physician specialities and disease subtypes.

Atherothrombosis is now clearly established as the

underlying pathology for stroke, transient ischaemic

Even though

the majority of

REACH registry

patients were

receiving

recommended

treatments,

the event rates

were still high

1786 Editorials


Documents

Intervening on HDL-C: Is it possible? Does it work?