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Review | Clinician's Corner

High-Density Lipoprotein as a Therapeutic Target A Systematic Review

Inder M. Singh, MD, MS; Mehdi H. Shishehbor, DO, MPH; Benjamin J. Ansell, MD
JAMA. 2007;298(7):786-798. doi:10.1001/jama.298.7.786.
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Published online

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.

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Figure 1. Selection Process for Study Inclusion
Graphic Jump Location

See “Data Acquisition” for search terms and details of selection process.
aIncludes 1 study identified after the May 2007 search cutoff.4
bUsing inclusion criteria 1 and 2 (see “Data Acquisition”).

Figure 2. Overview of Reverse Cholesterol Transport and High-Density Lipoprotein Metabolism
Graphic Jump Location

ABCA1 indicates adenosine triphosphate–binding cassette transporter A1; ABCG1, adenosine triphosphate–binding cassette transporter G1; apo, apolipoprotein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LDL-R, LDL receptor; LPL, lipoprotein lipase; SR-B1, scavenger receptor type B1; VLDL, very low-density lipoprotein.




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