Here is the accompanying editorial:
HDL cholesterol and cardiovascular risk
bmj.com
Treatments can increase HDL cholesterol, but do not independently reduce risk
History tends to repeat itself, in the medical sciences as in other domains. In the linked systematic review (doi:10.1136/bmj.b92), Briel and colleagues put high density lipoprotein (HDL) cholesterol into perspective as a marker of risk, and their findings evoke memories of other risk markers.1 Like HDL cholesterol, premature ventricular contractions are a validated risk marker for cardiovascular disease. Such contractions indicate an increased risk for adverse cardiovascular outcomes in the general population and in patients presenting with cardiovascular disease.2 3 Yet specific treatments that eliminate these contractions do not decrease the risk for adverse outcomes and can even increase risk.4 Thus, modifying the known marker of increased risk does not necessarily modify the risk itself.
Briel and colleagues demonstrate this phenomenon for HDL cholesterol in a meta-regression study of 108 clinical trials that assessed more than 300 000 patients and several lipid modifying treatments.1 They found that although some of the treatments increased concentrations of HDL cholesterol, these increases were not independently associated with a decrease in cardiovascular risk. This is in contrast to the decreases in low density lipoprotein (LDL) cholesterol that occurred with many of the treatments evaluated, which were strongly associated with reduced risk of cardiovascular disease.
Briel and colleagues admit to the limitations of their findings—their meta-regression analysis used aggregated study data rather than individual patient data, and their analytical power was constrained by the modest change and variability in mean HDL cholesterol concentrations in available studies (mean increase of 0.04 mmol/l; standard deviation 0.08). These findings indicate that lipid modifying interventions should target LDL cholesterol, not HDL cholesterol, to modify cardiovascular risk.
Should we be surprised? At first glance the findings of trials of HDL modifying treatments give reason for doubt about the merit of targeting HDL cholesterol for risk modification. Drugs such as fibrates and niacin increased HDL cholesterol and decreased cardiovascular risk in some trials,5 6 whereas others, such as hormone replacement therapy and the cholesterol ester transfer protein inhibitor torcetrapib, increased HDL cholesterol concentrations but also seemed to increase the risk of cardiovascular events.7 8 This divergence of effects across drug classes raises the possibility that different HDL subfractions have differing effects or that HDL function might be a better surrogate marker than the concentration of HDL cholesterol.9 Alternatively, it may be that the effects of the various drugs assessed are mediated through mechanisms other than HDL cholesterol. Briel and colleagues’ synthesis of the existing trials shows that HDL cholesterol is a surrogate marker, for which drug induced changes are not consistently associated with a change in risk of cardiovascular disease.
The clinical message of these findings is relatively simple and consistent with clinical practice guidelines. LDL cholesterol should be the primary target of lipid lowering treatments. But does it mean that clinicians should not try to increase HDL in their patients? This study does not prove that increasing HDL in selected patients with low HDL cholesterol has no value, because the meta-regression analysed mean HDL cholesterol changes in each trial only. Furthermore, several non-drug interventions that increase HDL—such as physical activity, smoking cessation, and moderate alcohol consumption—consistently decrease coronary risk,10 11 although factors other than increases in HDL have a role in their cardioprotective effects. These lifestyle interventions should be the first strategy to increase HDL in clinical practice, especially because they improve other health outcomes and have no side effects.
It is less clear whether low HDL cholesterol concentrations should be treated with drugs in patients already receiving targeted treatment for LDL cholesterol (with a statin, for example), because efficacy and safety data on combined treatments are limited. The results of future trials assessing the combination of statins and fibrates on clinical end points in broader and less selected populations will provide valuable information on the safety and efficacy of this combination.12
History does indeed repeat itself, and it will again as new biomarkers are explored as risk indicators for various diseases. But the demonstration that a marker is independently associated with risk does not mean that treatments that modify levels of the marker will also modify clinical risk. Clinicians and medical scientists need to keep these lessons of history in mind as they critically consider the value of new treatments and biomarkers.
Cite this as: BMJ 2009;338:a3065
William A Ghali, professor1, Nicolas Rodondi, senior lecturer2
1 Departments of Medicine and Community Health Sciences, Faculty of Medicine, University of Calgary, Calgary, AB, Canada, T2N 4N1, 2 Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, CH1011, Switzerland
wghali@ucalgary.ca
Research, doi:10.1136/bmj.b92
Competing interests: NR has presented academic rounds at Swiss hospitals where speaker fees were provided by Pfizer, AstraZeneca, and Merck-Schering-Plough. He also leads an investigator initiated study on quality of care in Switzerland that receives support from Pfizer.
Provenance and peer review: Commissioned; not externally peer reviewed.
References
1. Briel M, Ferreira-Gonzalez I, You JJ, Karanicolas PJ, Akl EA, Wu P, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 2009;338:b92.[Abstract/Free Full Text]
2. Bikkina M, Larson MG, Levy D. Prognostic implications of asymptomatic ventricular arrhythmias: the Framingham heart study. Ann Intern Med 1992;117:990-6.[ISI][Medline]
3. Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Frederiksen BS, Davanlou M, et al. Ventricular arrhythmias and risk of death and acute myocardial infarction in apparently healthy subjects of age 55 or older. Am J Cardiol 2006;97:1351-7.[CrossRef][ISI][Medline]
4. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406-12.[Abstract]
5. Birjmohun RS, Hutten BA, Kastelein JJ, Stroes ES. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2005;45:185-97.[Abstract/Free Full Text]
6. Saha SA, Kizhakepunnur LG, Bahekar A, Arora RR. The role of fibrates in the prevention of cardiovascular disease—a pooled meta-analysis of long-term randomized placebo-controlled clinical trials. Am Heart J 2007;154:943-53.[CrossRef][ISI][Medline]
7. Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304-16.[Abstract/Free Full Text]
8. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.[Abstract/Free Full Text]
9. DeGoma EM, deGoma RL, Rader DJ. Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches. J Am Coll Cardiol 2008;51:2199-211.[Abstract/Free Full Text]
10. Sofi F, Cesari F, Abbate R, Gensini GF, Casini A. Adherence to Mediterranean diet and health status: meta-analysis. BMJ 2008;337:a1344.[Abstract/Free Full Text]
11. Manson JE, Hu FB, Rich-Edwards JW, Colditz GA, Stampfer MJ, Willett WC, et al. A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women. N Engl J Med 1999;341:650-8.[Abstract/Free Full Text]
12. ACCORD. ACCORD purpose. 2006. www.accordtrial.org/public/index.cfm. |
