All you need to read in the other general journalsBMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e3578 (Published 23 May 2012) Cite this as: BMJ 2012;344:e3578
All rapid responses
Challenging the traditional concept that raising high density lipoprotein (HDL) levels reduces the risk of myocardial infarction, a mendelian randomization study did not show any advantage of an isolated HDL increase .
With the identification of several single nucleotide polymorphisms (SNP’s) affecting lipid metabolism through genome wide association studies, it was suggested that several of these genetic loci which increase HDL levels might confer a cardio-protective role. In particular, carriers of the LIPG 396Ser allele are found to have significantly increased HDL levels whereas other lipid profiles appear similar to those who lack this allele. These genetic polymorphisms, unfortunately do not translate into a reduced MI risk clinically.
This observational study published in Lancet last week adds to the growing evidence that increasing HDL levels alone do not co-relate clinically with improved outcomes whether in primary or secondary prevention.
Low density lipoproteins (LDL) have been proven by several well designed, large scale studies to correlate directly with the increased risk of coronary artery disease (CAD) and have hence traditionally been termed as “bad” cholesterol . On the other hand high density lipoproteins (HDL), by virtue of their phenomenon of “reverse cholesterol transport” have been postulated to be inversely linked with CAD and hence decreased risk of myocardial infarction (MI), hence termed as “good cholesterol”.
However, despite the postulated hypothesis, there has been little evidence to directly support that increasing HDL levels do co-relate clinically with improved outcomes whether in primary or secondary prevention. This is due to the fact that patients with low HDL levels are more prone to obesity and diabetes, hence making it difficult to delineate whether the increased risk of CAD is due to lower HDL levels or increased insulin resistance (or both) .
Since statins only modestly raise HDL levels (around 5%), the use of niacin (which increase HDL levels by 30-35%) both in conjunction with statins and as monotherapy has been investigated. Unfortunately, the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM HIGH) trial had to be terminated early because it did not show any improvements in the primary end points (first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome) .
In the present study, the frequency of LIPG 396Ser allele allele in 95 407 controls and 20 913 cases with a history of MI was 2.6%. Despite significantly greater HDL, the frequency of MI was similar between the 2 groups.
In an accompanying editorial  in the Lancet, Harrison and colleagues stated "genetically raised HDL-cholesterol concentrations do not seem to reduce risk of coronary heart disease—an observation that calls into question whether raising HDL cholesterol therapeutically would translate into the expected clinical benefit."
In the summary of the study, Dr. Voight et al stated that “some genetic mechanisms that raise HDL cholesterol do not lower risk of myocardial infarction. Hence, interventions (lifestyle or pharmacological) that raise plasma HDL cholesterol cannot be assumed ipso facto to lead to a corresponding benefit with respect to risk of myocardial infarction.”
1. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 201210.1016/S0140-6736(12)60312-2. published online May 17
2. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA. 1986;256(20):2835-2838
3. Cannon CP. High-density lipoprotein cholesterol as the Holy Grail. JAMA. 2011 Nov 16;306(19):2153-5.
4. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255-67. Epub 2011 Nov 15.
5. Harrison SC, Holmes MV, Humphries SE. Mendelian randomisation, lipids, and cardiovascular disease. Lancet. 2012 May 16.
Competing interests: No competing interests