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progression in the placebo group. The absence of a *Erik S G Stroes, Diederik F van Wijk
beneficial effect on parameters of the aortic vessel wall Department of Vascular Medicine, Academisch Medisch
Centrum, Meibergdreef, 1105 AZ Amsterdam, Netherlands
might be due to the heterogeneity of anti-atherosclerotic
e.s.stroes@amc.uva.nl
effects or the small sample size. A similar study with
We declare that we have no conflicts of interest.
anacetrapib, a more potent CETP inhibitor, could resolve
1 Camont L, Chapman MJ, Kontush A. Biological activities of HDL
this issue, although the simultaneous decrease of LDL-C subpopulations and their relevance to cardiovascular disease.
Trends Mol Med 2011; published online Aug 11. DOI:10.1016/
by anacetrapib complicates interpretation of the exact j.molmed.2011.05.013.
role of HDL-C.11 2 Barter PJ, Caulfield M, Eriksson M, et al, for the ILLUMINATE Investigators.
Effects of torcetrapib in patients at high risk for coronary events.
In addition to MRI, patients in Fayad and colleagues’ N Engl J Med 2007; 357: 2109–22.
study were also assessed with ¹⁸FDG-PET/CT. FDG 3 Rader DJ. Illuminating HDL—is it still a viable therapeutic target?
N Engl J Med 2007; 357: 2180–83.
uptake indicates inflammation of the arterial wall, 4 Fayad ZA, Mani V, Woodward M, et al, for the dal-PLAQUE Investigators.
which is most probably attributable to accumulation Safety and efficacy of dalcetrapib on atherosclerotic disease using novel
non-invasive multimodality imaging (dal-PLAQUE): a randomised
within plaque macrophages.12 Whether CETP-mediated clinical trial. Lancet 2011; published online Sept 12. DOI:10.1016/S0140-
6736(11)61383-4.
increase in HDL would lead to pro-inflammatory HDL 5 Hu X, Dietz JD, Xia C, et al. Torcetrapib induces aldosterone and cortisol
particles has long been debated. The decrease in carotid production by an intracellular calcium-mediated mechanism
independently of cholesteryl ester transfer protein inhibition.
FDG uptake observed in the dalcetrapib group implies Endocrinology 2009; 150: 2211–19.
an anti-inflammatory effect of the HDL-C particle, 6 Stroes ES, Kastelein JJ, Benardeau A, et al. Dalcetrapib: no off-target toxicity
on blood pressure or on genes related to the renin-angiotensin-aldosterone
which is supported by the inverse correlation between system in rats. Br J Pharmacol 2009; 158: 1763–70.
7 Sofat R, Hingorani AD, Smeeth L, et al. Separating the mechanism-based
HDL-C increase and FDG uptake in the present study. and off-target actions of cholesteryl ester transfer protein inhibitors with
Counterintuitively, markers of systemic inflammation CETP gene polymorphisms. Circulation 2010; 121: 52–62.
8 Vergeer M, Bots ML, van Leuven SI, et al. Cholesteryl ester transfer protein
did not decrease in the dalcetrapib group, underscoring inhibitor torcetrapib and off-target toxicity: a pooled analysis of the Rating
the poor correlation between systemic and vessel wall Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor
(RADIANCE) trials. Circulation 2008; 118: 2515–22.
inflammation. These findings indicate that the time 9 Stein EA, Stroes ES, Steiner G, et al. Safety and tolerability of dalcetrapib.
has come to assess the effect of selective, potent anti- Am J Cardiol 2009; 104: 82–91.
10 Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid
inflammatory drugs on vessel wall inflammation and atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007;
356: 1620–30.
cardiovascular outcome. This effect is currently being
11 Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with
tested in the CANTOS study with an antagonist of or at high risk for coronary heart disease. N Engl J Med 2010; 363: 2406–15.
12 Rudd JH, Hyafil F, Fayad ZA. Inflammation imaging in atherosclerosis.
the interleukin 1β receptor in patients with cardio- Arterioscler Thromb Vasc Biol 2009; 29: 1009–16.
vascular disease.13 13 Libby P, Ridker PM, Hansson GK. Progress and challenges in translating
the biology of atherosclerosis. Nature 2011; 473: 317–25.
As we await the final verdict on dalcetrapib in 2013,
when the DAL-OUTCOME study will provide data on
cardiovascular endpoints in 15 600 patients, the findings
of Fayad and colleagues bring us one step higher on the
ladder of CETP research, after its free fall since 2006.
that they had not recovered. So, further improvements 3 van Tulder MW, Koes B, Malmivaara A. Outcome of non-invasive treatment
modalities on back pain—an evidence-based review. Eur Spine J 2006;
are desirable. Hill and colleagues are to be applauded 15 (suppl 1): S64–S81.
for showing that improvements in the management of 4 Kuijpers T, van Middelkoop M, Rubinstein SM, et al. A systematic review on
the effectiveness of pharmacological interventions for chronic non-specific
low back pain in primary care are feasible. Clinicians and low-back pain. Eur Spine J 2011; 20: 40–50.
researchers now face the challenge of implementing and 5 van Middelkoop M, Rubinstein SM, Kuijpers T, et al. A systematic review on
the effectiveness of physical and rehabilitation interventions for chronic
further optimising the new approach. non-specific low back pain. Eur Spine J 2011; 20: 19–39.
6 Rubinstein SM, van Middelkoop M, Kuijpers T, et al. A systematic review on
the effectiveness of complementary and alternative medicine for chronic
Bart Koes non-specific low-back pain. Eur Spine J 2010; 19: 1213–28.
Department of General Practice, Erasmus University Medical 7 Foster NE, Hill JC, Hay EM. Subgrouping patients with low back pain in
primary care: are we getting any better at it? Man Ther 2011; 16: 3–8.
Centre, 3000 CA Rotterdam, Netherlands 8 Kamper SJ, Maher CG, Hancock MJ, Koes BW, Croft PR, Hay E.
b.koes@erasmusmc.nl Treatment-based subgroups of low back pain: a guide to appraisal
of research studies and a summary of current evidence.
I declare that I have no conflicts of interest.
Best Pract Res Clin Rheumatol 2010; 24: 181–91.
1 Hill JC, Whitehurst DGT, Lewis M, et al. Comparison of stratified primary 9 Stanton TR, Hancock MJ, Maher CG, Koes BW. Critical appraisal of clinical
care management for low back pain with current best practice (STarT prediction rules that aim to optimize treatment selection for
Back): a randomised controlled trial. Lancet 2011; published online Sept 29. musculoskeletal conditions. Phys Ther 2010; 90: 843–54.
DOI:10.1016/S0140-6736(11)60937-9.
2 Koes BW, van Tulder M, Lin CW, Macedo LG, McAuley J, Maher C.
An updated overview of clinical guidelines for the management of
non-specific low back pain in primary care. Eur Spine J 2010; 16: 2075–94.