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HDL Raising Therapy

HDL-Raising Therapy

  • Although statins reduce the risk of heart attack, most CVD (cardiovascular disease) events still occur despite statin treatment. This residual risk seen in statin-treated patients may be partly explained by low HDL-C levels.1, 2
  • Imaging trials have provided evidence of the combined influence of HDL-C and LDL-C on surrogate end points, and it is hoped that improvements in both lipid parameters will also lead to improvements in clinical event rates and provide a more effective strategy for reducing CVD events and death.3 
  • The preponderance of the evidence supports the need to raise HDL-C in patients at risk for CVD events. However, the data on the effects of increasing HDL-C levels on CVD events are fewer and less clear than those for LDL-C. Ongoing trials of adding HDL-C raising agents to statins (statin and niacin combination therapy) are under investigation as a possible approach to reduce the residual risk that persists with statin monotherapy. 
  • The available options for raising the HDL-C are relatively few. Lifestyle interventions are safe but only modestly increase HDL. While HDL-C levels may be increased up to 10% by implementing therapeutic lifestyle changes including weight reduction, exercise, smoking cessation and moderate alcohol consumption, most patients will require medications when targets are set.  The best treatment currently available is niacin.4 Fibrates have shown benefit in people with low HDL-C and high triglyceride levels.

Decreasing Role of HDL with Very Low LDL

  • Despite a marked reduction (up to 60%) in LDL-C, more than 50% of patients continue to have CVD events. This high residual risk in statin-treated patients initiated the search for new ways to reduce CVD risk.
  • Statins reduce CVD events in patients with low HDL-C, and the benefit of statins on event reduction may be related to their effects on HDL-C and apo A-I.  In a meta-analysis of more than 90,000 subjects in 14 randomized trials of statin therapy, statins reduced CVD risk by 21- 22% across all categories of baseline HDL-C. 5 However, CVD risk was 50% greater in statin-treated patients with HDL-C < 35 mg/dL than in placebo patients with HDL-C > 43 mg/dL indicating that patients with low HDL-C have residual risk despite statin therapy.5
  • In the TNT (Treating to New Targets) trial, a large number of subjects achieved LDL-C <70mg/dL with atorvastatin therapy. However those in the lowest quintile for HDL-C (at 3 months on treatment) had greater CVD risk (38%) than those in the highest quintile.6
  • In sharp contrast, the CVD risk from low HDL-C was reduced or eliminated in those who achieved very low levels of LDL-C in JUPITER Trial.  In this trial, subjects had a low baseline LDL-C level of 180 mg/dL that was reduced to a median level of 55 mg/dL with rosuvastatin 20 mg/d.7
  • In the new analysis, the 8900 subjects on placebo, with high HDL levels, were protected from CVD events; those in the lowest HDL group having about double the risk than the group with the highest HDL levels. But among the other 8900 who took Crestor and brought the LDL-C to 55 mg/dl, no links were seen between their HDL levels and their risk of heart attack or stroke.7
  • Rosuvastatin (Crestor) 20 mg/d reduces LDL up to 52%; it also raises HDL by up to 14%.7 The mean LDL-C was 55 mg/dl among the JUPITER subjects who received rosuvastatin 20 mg/d.
  • Patients on statin drugs who reduce their LDL-C to very low levels may not need to be so concerned about boosting their HDL-C levels for protection against cardiovascular disease, according to this study.
  • The AIM HIGH Study also showed no benefit of raising HDL-C. In this study, all patients received simvastatin, which was titrated to LDL-C of 40-80 mg/dl (mean LDL-C 71mg/dL, mean HDL 35mg/dL, mean TG 161mg/dL, and non-HDL-C 107mg/dL). Some patients also received ezetimibe to achieve this goal. Patients were then randomized to extended-release niacin, 1500-2000 mg daily (n = 1,718) compared with placebo (n = 1,696).
  • No reduction in CVD outcome was found with those who received niacin on top of aggressively controlled LDL-C. This is in contrast to earlier studies, all of which had substantially higher LDL-C.8 Both JUPITER and AIM HIGH Studies support that the primary focus of our treatment strategies should be reduction of LDL.
  • Although low HDL may not matter in those with very low LDL levels, low HDL remains an important predictor of risk in the general population since most patients treated with statins do not achieve LDL 55 mg/dl or below.9 


1. Jafri H, Alsheikh-Ali AA, Karas RH. Meta-analysis: statin therapy does not alter the association between low levels of high-density lipoprotein cholesterol and increased cardiovascular risk. Ann Intern Med. Dec 21 2010;153(12):800-808.

2. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. Nov 13 2010;376(9753):1670-1681.

3. Negi S, Ballantyne CM. Insights from recent meta-analysis: role of high-density lipoprotein cholesterol in reducing cardiovascular events and rates of atherosclerotic disease progression. J Clin Lipidol. Sep-Oct 2010;4(5):365-370.

4. Natarajan P, Ray KK, Cannon CP. High-density lipoprotein and coronary heart disease: current and future therapies. J Am Coll Cardiol. Mar 30 2010;55(13):1283-1299.

5. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. Oct 8 2005;366(9493):1267-1278.

6.  Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. Sep 27 2007;357(13):1301-1310.

7. Ridker PM, Genest J, Boekholdt SM, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet. Jul 31 2010;376(9738):333-339.

8. 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(22):1583-1592.

9. Ridker PM, Genest J, Boekholdt SM, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet. Jul 31 2010;376(9738):333-339.

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