HDL Cholesterol: Why Higher Levels No Longer Equal Lower Risk

June 20, 2012

A genetic analysis questions the benefits of raising HDL-C levels to reduce the risk of MI and of the value of HDL-C as a surrogate marker of risk.

A large genetic analysis reported in the May 17, 2012, issue of the Lancet1showed no association between naturally high levels of HDL cholesterol (HDL-C) and a reduced risk of heart disease, raising even more questions about available HDL-raising strategies and the pharmaceutical research and development programs focused on bringing new agents to market.

The results are the third data set in the past several years to cast doubt on the widely held HDL-C hypothesis: HDL protects against atherosclerosis. The AIM-HIGH study2 was stopped early when there was no clinical benefit seen from the addition of niacin to statin therapy in patients with established cardiovascular disease, despite significant improvement in levels of HDL-C.3 More recently, a phase 3 clinical trial of the cholesteryl ester transfer protein inhibitor dalcetrapib (dal-OUTCOMES)4 also was stopped for lack of efficacy.5

• Do the disappointing results of the genetic analysis constitute a third strike and effectively “bench” HDL-raising as a means to help reduce cardiovascular risk?
• What important questions do these studies raise about the cardioprotective mechanisms of HDL-C?
• What should primary care physicians tell patients who ask about current HDL-raising strategies?  
• Should those strategies be modified while scientists re-think the HDL hypothesis and re-focus investigation? 

To answer these questions and put the issue into clinical perspective for primary care physicians, here are Drs Christopher Cannon and Payal Kohli. Dr Cannon, a senior investigator with the TIMI Study Group, is Editor-in-Chief of Cardiosource Science and Quality. He is also Professor of Medicine at Harvard Medical School and Associate Physician in the Cardiovascular Division of Brigham and Womens’ Hospital in Boston. Dr Kohli graduated from Harvard Medical School, completed her internal medicine training in Boston, and is currently a fellow in cardiovascular medicine at the University of California San Francisco.


Higher HDL, Not Lower Risk

Take-Home Points
1. The results of the genetic study challenge a number of established views about HDL-C: first is the concept that raising plasma HDL-C levels should translate into reduction in risk of MI and, second is the belief that HDL-C is an appropriate surrogate measure for risk of MI in intervention trials.
2. The genetic data do not place into question the value of using low HDL-C levels as a marker of risk for MI. Continue to check HDL-C levels, and for now, management of patients with low values should reinforce lifestyle change (eg, improved diet, regular exercise, weight loss, smoking cessation when relevant) and focus on meeting LDL-C targets.
3. Research is still ongoing for new drugs that raise HDL-C levels.


1. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: A Mendelian randomization study. Lancet. 2012;DOI:10.1016/S0140-6736(12)60312-2.
2. The AIM-HIGH investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255-2267.
3. Michos ED, Sibley CT, Baer JT, et al. Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events: reconciling the AIM-HIGH trial with previous surrogate endpoint trials. J. Am. Coll. Cardiol. 2012; 59:2058-2064.
4. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J. 2009;158:896–901.
5. Roche, Inc. Roche provides update on Phase III study of dalcetrapib [press release]. May 12, 2012. Available at: http://www.roche.com/media/media_releases/med-cor-2012-05-07.htm