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International Chair on Cardiometabolic Risk
My Healthy Waist

Editorial: Treating the patient with low HDL-cholesterol: Are we chasing the right target?

By Jean-Pierre Després, PhD, FAHA, FIAS, Scientific Director, International Chair on Cardiometabolic Risk, Professor, Department of Kinesiology, Université Laval, Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada

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 [14].

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 [19]) 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 [17]. 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 [14]. Would fibrate therapy be helpful in those patients? Subgroup analyses from the VA-HIT trial [20] 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 [8] 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 [22].

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.

References

  1. Castelli WP, Doyles JT and Gordon T. HDL-cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation 1977; 55: 767-72. PubMed ID: 191215
  2. Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease: the Framingham study. Am J Med 1977; 62: 707-14. PubMed ID: 193398
  3. Miller NE, Forde OH, Thelle DS, et al. The Tromso Heart Study: high-density lipoprotein as a protective factor against coronary heart disease: a prospective case-control study. Lancet 1977; 1: 965-7. PubMed ID: 67464
  4. Castelli WP. Cholesterol and lipids in the risk of coronary artery disease–the Framingham Heart Study. Can J Cardiol 1988; 4: 5A-10A. PubMed ID: 3179802
  5. Assmann G and Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Am J Cardiol 1992; 70: 733-7. PubMed ID: 1519522
  6. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341: 410-8. PubMed ID: 10438259
  7. Bezafibrate Infarction Prevention (BIP) study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000; 102: 21-7. PubMed ID: 10880410
  8. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366: 1849-61. PubMed ID: 16310551
  9. Garg A and Grundy SM. Nicotinic acid as therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. JAMA 1990; 264: 723-6. PubMed ID: 2374275
  10. Brown BG. Expert commentary: niacin safety. Am J Cardiol 2007; 99: 32C-4C. PubMed ID: 17368276
  11. Brewer HB, Jr. Increasing HDL Cholesterol Levels. N Engl J Med 2004; 350: 1491-4. PubMed ID: 15071124
  12. Barter PJ, Nicholls S, Rye KA, et al. Antiinflammatory properties of HDL. Circ Res 2004; 95: 764-72. PubMed ID: 15486323
  13. Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest 2006; 116: 3090-100. PubMed ID: 17143322
  14. 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. PubMed ID: 17387129
  15. Castelli WP, Garrison RJ, Wilson PWF, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA 1986; 256: 2835-8. PubMed ID: 3773200
  16. Lamarche B, Moorjani S, Cantin B, et al. Associations of HDL2 and HDL3 subfractions with ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Arterioscler Thromb Vasc Biol 1997; 17: 1098-105. PubMed ID:  9194760
  17. Després JP and Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444: 881-7. PubMed ID: 17167477
  18. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112: 2735-52. PubMed ID: 16157765
  19. Lemieux I, Pascot A, Prud’homme D, et al. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol 2001; 21: 961-7. PubMed ID: 11397704
  20. Robins SJ, Rubins HB, Faas FH, et al. Insulin resistance and cardiovascular events with low HDL cholesterol. The Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care 2003; 26: 1513-7. PubMed ID: 12716814
  21. Tenenbaum A, Motro M, Fisman EZ, et al. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med 2005; 165: 1154-60. PubMed ID: 15911729
  22. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001; 345: 1583-92. PubMed ID: 11757504
  23. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 537-44. PubMed ID: 9096977
  24. Paffenbarger RS, Jr., Wing AL and Hyde RT. Physical activity as an index for heart attack risk in college Alumni. Am J Epidemiol 1978; 108: 161-75. PubMed ID: 707484
  25. Morris JN, Chave SPW, Adam C, et al. Vigorous exercise in leisure-time and the incidence of coronary heart disease. Lancet 1973; 1: 333-9. PubMed ID: 4121934
  26. Katzmarzyk PT, Leon AS, Wilmore JH, et al. Targeting the metabolic syndrome with exercise: evidence from the HERITAGE Family Study. Med Sci Sports Exerc 2003; 35: 1703-9. PubMed ID: 14523308
  27. Leon AS and Sanchez OA. Response of blood lipids to exercise training alone or combined with dietary intervention. Med Sci Sports Exerc 2001; 33: S502-15; discussion S28-9. PubMed ID: 11427777
  28. Ross R, Dagnone D, Jones PJ, et al. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med 2000; 133: 92-103. PubMed ID: 10896648
  29. Kraus WE, Houmard JA, Duscha BD, et al. Effects of the amount and intensity of exercise on plasma lipoproteins. N Engl J Med 2002; 347: 1483-92. PubMed ID: 12421890
  30. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403. PubMed ID: 11832527
  31. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343-50. PubMed ID: 11333990
  32. Després JP, Golay A and Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353: 2121-34. PubMed ID: 16291982
  33. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 2006; 295: 761-75. PubMed ID: 16478899
  34. Scheen AJ, Finer N, Hollander P, et al. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006; 368: 1660-72. PubMed ID: 17098084
  35. Van Gaal LF, Rissanen AM, Scheen AJ, et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365: 1389-97.  PubMed ID: 15836887
  36. Maeda K, Noguchi Y and Fukui T. The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis. Prev Med 2003; 37: 283-90. PubMed ID: 14507483
  37. Stubbe I, Eskilsson J and Nilsson-Ehle P. High-density lipoprotein concentrations increase after stopping smoking. Br Med J (Clin Res Ed) 1982; 284: 1511-3. PubMed ID: 6805587