| Author | Mazzone T. |
| Title | HDL cholesterol and atherosclerosis |
| Full source | Lancet 2007;370:107-8 |
| Text |
In observational studies, the strong relation between HDL cholesterol concentration and risk of cardiovascular disease has been shown repeatedly. This relation gave rise to the idea that HDL cholesterol is antiatherogenic and thus reduces the risk of cardiovascular disease. This conclusion has been supported by in-vitro studies providing potential mechanisms; however, which mechanism is the most important for atheroprotection in vivo is unknown. Some interventions that raise HDL cholesterol can reduce the risk of cardiovascular disease. Lifestyle changes, such as avoidance of smoking, maintenance of normal bodyweight, and exercise, can raise HDL cholesterol, albeit by a small amount. The benefit of drugs that raise HDL cholesterol to reduce atherosclerosis, however, needs more investigation. HDL cholesterol is compositionally and metabolically complex,1–3 and many aspects of its metabolism are species-specific, which makes animal models less than ideal. Several classes of drugs increase HDL cholesterol in human beings by 5–20% (table).4–12 Inhibition of cholesterol ester transfer protein (CETP) is potentially useful because populations with CETP mutations have very high HDL cholesterol. However, that such inhibition would favourably affect cardiovascular diseases was not consistently supported by the rates of such diseases in these populations. Drugs
with predominant lipid effect on HDL cholesterol
A large clinical trial to assess the effect of torcetrapib on cardiovascular diseases was interrupted because of excess mortality in patients on torcetrapib.12 Two other imaging trials have assessed the effect of torcetrapib. One study measured intravascular ultrasound of the coronary arteries in patients undergoing clinically indicated cardiac catheterisation,3 whereas the other measured carotid intima-media thickness in patients with familial hypercholesterolaemia.11 Both studies failed to show benefit with torcetrapib. Patients with mixed dyslipidaemia, as studied by Kastelein and colleagues, are the ideal population to test drugs that increase HDL cholesterol. These patients commonly present with low HDL cholesterol, and their excess risk for cardiovascular diseases is not completely eliminated by treatment that lowers LDL cholesterol. Therefore, failure of torcetrapib to reduce progression of atherosclerosis in this population, despite a 62% rise in HDL cholesterol, is informative. Changes in systolic blood pressure have powerful effects on atherosclerosis, and torcetrapib-related increases in blood pressure might have mitigated a beneficial effect of increased HDL cholesterol. However, as discussed by Kastelein, extrapolation from other trials that measured carotid intima-media thickness makes it unlikely that the adverse effect of this rise of blood pressure could have eliminated the beneficial effect of a 62% increase of HDL cholesterol if HDL particles produced by CETP inhibition conferred the degree of atheroprotection predicted by observational studies. What lesson can be learned from treatment that increases HDL cholesterol? Some CETP inhibitors that do not increase blood pressure might be of benefit in atherosclerosis. However, the beneficial effect is unlikely to be of the size expected for the large increases in HDL cholesterol produced by such inhibition. Future analysis of the relation between HDL cholesterol or blood pressure on the one hand and cardiovascular disease or atherosclerosis on the other will be important. The failure of imaging trials to show a difference between treatment with atorvastatin alone compared with torcetrapib and atorvastatin in combination, considering the higher event rate in the clinical endpoint trial, also needs to be explained. This discrepancy might be related to different populations in the studies. Alternatively, treatment with torcetrapib might neither improve nor worsen atherosclerosis, and the clinical event rate might rise if such treatment increased the propensity of atherosclerotic lesions to rupture or thrombose. The
failure of torcetrapib reduces the hope of finding a simple way for raising
atheroprotective HDL cholesterol. The complexity of the HDL particle and
the uncertainty about which of its in-vitro functions is key for atheroprotection
means that large clinical trials are needed before the clinical value
of any pharmacological approach to raise HDL cholesterol can be accepted.
Present understanding of physiology and metabolism of HDL cholesterol
suggests several additional regulatory targets for raising HDL cholesterol.
Targeting of different regulatory nodes produces HDL cholesterol particles
of different composition and possibly different function. The use of surrogate
imaging endpoints, such as carotid intima-media thickness, might provide
important information that could focus clinical trial activity on the
most promising drug candidates References
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