For more than three decades, lipidologists have emphasized the added value of measuring HDL-cholesterol in the evaluation of coronary heart disease (CHD) risk. There is now substantial epidemiological evidence that for any given LDL-cholesterol concentration a low HDL-cholesterol concentration is predictive of an increased risk of CHD in both men and women [1-5]. Thus, therapeutic modalities to increase HDL-cholesterol levels (fibrates, niacin) have received considerable attention with the hope of optimally reducing CHD risk among patients treated with LDL lowering agents (statins). Mixed results have been published with fibrate therapy regarding its benefits on hard clinical outcomes [6-8] whereas the use of niacin has been limited by its side effects which include flushing, hepatotoxicity and induction of impaired insulin action, which make its use in diabetic or prediabetic patients quite problematic [9, 10].
Thus, other modalities to increase HDL have been examined. Because of the spectacular HDL-cholesterol raising properties of CETP inhibitors and considering the plethora of studies showing that HDL had anti-inflammatory, anti-thrombotic and anti-oxidant properties [11-13], investigators were eagerly looking forward to the results of clinical trials investigating the effects of the first CETP inhibitor under clinical development, torcetrapib, on clinical outcomes and on the progression/regression of atherosclerotic plaques measured by intravascular ultrasound (IVUS). The negative results of the recently published ILLUSTRATE trial require that we pause for a moment and re-examine the conceptual framework on which such therapy was developed .
Although epidemiological studies have clearly shown that a low HDL-cholesterol concentration is predictive of an increased risk of CHD [2, 15, 16], it is important to keep in mind that in clinical practice, a low HDL-cholesterol concentration is rarely seen in isolation. With the current epidemic of type 2 diabetes and overweight/obesity, it should be kept in mind that the most prevalent low HDL-cholesterol patient seen by clinicians is abdominally obese, sedentary, with insulin resistance and with hypertriglyceridemia [17, 18]. He/she also often has signs of inflammation (elevated CRP ) and a pro-thrombotic state, this condition being often described as the metabolic syndrome, the insulin resistance syndrome or more recently as a dysfunctional adipose tissue phenotype that we have described as visceral obesity . Thus, for this overwhelmingly prevalent low HDL-cholesterol patient at increased CHD risk, the question remains: Although his/her low HDL-cholesterol is predictive of an increased CHD risk, which treatment modality raising HDL will be cardioprotective? From the torcetrapib trials, we have learned that CETP inhibition, which incidentally produced tremendous increases in HDL-cholesterol levels, did not translate into clinical benefits . Would fibrate therapy be helpful in those patients? Subgroup analyses from the VA-HIT trial  and from the BIP study [7, 21] have suggested that abdominally obese, insulin resistant low HDL-cholesterol patients may be the right patient population for fibrate therapy but the equivocal results of the FIELD trial  have raised doubts about a consistent class effect in this population of patients and further analyses/studies are eagerly awaited to clarify this issue.
Angiographic trials have suggested that adding niacin to a statin may be beneficial but patients’ complaints about the cutaneous flushing and the impact of this drug on insulin resistance are issues that may limit the widespread use of this drug .
However, what if a low HDL-cholesterol concentration was mainly a “red light” on the panel of risk factors/markers, a warning sign that the patient is sedentary, may be smoking, insulin resistant, viscerally obese with the features of the insulin resistance/metabolic syndrome? We currently have no randomized trial showing that weight loss resulting from an intervention program would reduce CHD risk. However, we have substantial evidence that lean, physically active, insulin sensitive individuals are at much lower risk of diabetes and CHD [23-25]. Weight loss in insulin resistant viscerally obese patients has profound and comprehensive effects on all features of the metabolic syndrome (including a reduction in blood pressure) [26-29]. However, the clinician left with this therapeutic option currently has little help to induce a sustained weight loss and loss of visceral fat over time (years). Most clinical environments do not provide adequate support so that patients could develop skills over time to cope with their permissive “toxic” environment. Properly educated patients could make better food choices and be aware that there are numerous opportunities to be more physically active, when they are educated to think of it when exposed to fast food and sedentary environments. Incidentally, two large prevention of diabetes studies have shown the tremendous benefits of losing a few kilos and of dropping the waistline by a few centimeters on the patients’ profile and the risk of developing type 2 diabetes [30, 31].
In that regard, another class of drug, CB1 antagonists, have been shown to raise HDL-cholesterol [32-35] but let’s hope that lessons will be learned from the “torcetrapib story”. The HDL raising properties of this new class of agent should not be overemphasized or examined in isolation. Rather, it is more likely that the potential clinical benefits of this drug (if confirmed by clinical trials) may be explained by the fact that weight lost represents a more “physiological approach” to raise HDL-cholesterol as such change in HDL-cholesterol is accompanied by loss of abdominal fat, improved insulin sensitivity, reduced triglyceride levels, reduced inflammation, increase adiponectin and reduced blood pressure. The ongoing STRADIVARIUS trial will examine the effect of the first CB1 antagonist rimonabant on the progression/regression of the atherosclerotic plaque measured by IVUS. But again, it is probable that the patient who will benefit the most from this drug will be the low HDL-cholesterol patient who is also abdominally obese and insulin resistant. From the torcetrapib studies, it is unlikely that the potentially cardioprotective properties of this drug will be solely explained by its HDL-cholesterol raising properties.
We have therefore learned another lesson from Mother’s Nature. Let’s go back to the basics. A healthy diet and a physically active lifestyle represent the cornerstone of therapy for the prevalent low HDL-cholesterol abdominally obese patient. Furthermore, the low HDL-cholesterol patient who smokes should stop smoking as this will raise HDL-cholesterol levels [36, 37]. These are simple recommendations. Unfortunately, the medical system is currently ill-equipped to provide assistance to the high-risk sedentary abdominally obese patient. This problem represents a major barrier to the management of the growing epidemic of obesity and type 2 diabetes. Addressing this issue will require the involvement of all stakeholders as this question goes way beyond the ability of the medical system to cope with it.
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