High-density lipoprotein as a therapeutic target: a systematic review

JAMA. 2007 Aug 15;298(7):786-98. doi: 10.1001/jama.298.7.786.


Context: High-density lipoprotein cholesterol (HDL-C) is a cardiovascular risk factor that is gaining substantial interest as a therapeutic target.

Objectives: To review the current and emerging strategies that modify high-density lipoproteins (HDLs).

Data sources: Systematic search of English-language literature (1965-May 2007) in MEDLINE and the Cochrane database, using the key words HDL-C and apolipoprotein A-I and the subheadings reverse cholesterol transport, CVD [cardiovascular disease] prevention and control, drug therapy, and therapy; review of presentations made at major cardiovascular meetings from 2003-2007; and review of ongoing trials from ClinicalTrials.gov and current guidelines from major cardiovascular societies.

Study selection and data extraction: Study selection was prioritized to identify randomized controlled trials over meta-analyses over mechanistic studies; identified studies also included proof-of-concept studies and key phase 1 through 3 trials of novel agents. Study eligibility was assessed by 2 authors; disagreements were resolved by consensus with the third.

Data synthesis: Of 754 studies identified, 31 randomized controlled trials met the inclusion criteria. Currently available therapeutic and lifestyle strategies, when optimized, increase HDL-C levels by 20% to 30%. While basic and small pilot studies have shown promise, proof that increasing HDL-C levels confers a reduction in major cardiovascular outcomes independent of changes in levels of low-density lipoprotein cholesterol or triglycerides has been more elusive. Some novel therapeutic agents in human studies appear to effectively increase HDL-C levels, whereas other novel strategies that target HDL metabolism or function may have minimal effect on HDL-C levels.

Conclusions: At present there is modest evidence to support aggressively increasing HDL-C levels in addition to what is achieved by lifestyle modification alone. Ongoing clinical trials that target specific pathways in HDL metabolism may help expand cardiovascular treatment options.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Anticholesteremic Agents / pharmacology
  • Anticholesteremic Agents / therapeutic use*
  • Apolipoprotein A-I / blood
  • Atherosclerosis / blood
  • Atherosclerosis / epidemiology
  • Biological Transport
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / therapy*
  • Cholesterol, HDL / blood*
  • Cholesterol, HDL / metabolism
  • Humans
  • Lipoproteins, HDL / blood
  • Lipoproteins, HDL / metabolism
  • Macrophages / metabolism
  • Risk Factors
  • Risk Reduction Behavior*


  • Anticholesteremic Agents
  • Apolipoprotein A-I
  • Cholesterol, HDL
  • Lipoproteins, HDL