Two reviews reveal the lack of evidence for HDL-boosting agents

Cholesterol is transported in the bloodstream packaged with protein in the form of ‘lipoproteins’. There’s two main forms of lipoprotein in the blood: so-called ‘low density lipoprotein’-cholesterol (LDL) and ‘high density lipoprotein’-cholesterol (HDL). Traditionally, LDL has been said to be chiefly responsible for the depositing of cholesterol on the inside of the arteries and the development of cardiovascular diseases such as heart disease and stroke. HDL, on the other hand, has often been said to be a marker for the clearing of cholesterol from the inside of the arteries. Higher levels of HDL have traditionally been thought of as a good thing and indeed have been linked with better cardiovascular health outcomes.

The pharmaceutical industry has not been slow out of the blocks in its attempt to develop HDL-boosting therapies. After all, if higher HDL levels are associated with improved health, then raising HDL levels in the blood should be good for health, right? While sometimes persuasive, this logic is flawed on more than one level.

To begin with, just because HDL is associated with improved health outcomes, that doesn’t mean that it’s actually responsible for those outcomes. It might be that HDL is not so much a protective factor in cardiovascular disease, but a marker for protection.

We know, for instance, that high-carbohydrate diets can push up blood sugar levels and induce changes such as raised triglyceride levels, inflammation and ‘oxidative stress’ (free radical damage) that likely increase the risk of cardiovascular disease. High carbohydrate diets also tend to lead to lower HDL. So, not surprisingly, lower carbohydrate diets tend to raise HDL levels, and lower triglyceride levels, inflammation and oxidative stress. In people eating a low-carb diet HDL may be pleasingly on the high side.

But are the improved health outcomes associated with this down to the HDL or other markers associated with low-carb eating? We don’t know, I think, and that means we cannot be too sure that a drug or agent that pushes up HDL levels are necessarily a good thing. Also, a drug or agent may have untoward effects. So, even if cyanide turns out to be a good HDL-boosting agent, on balance one might judge that it’s overall effects on healthy are negative.

What all this boils down to is that what we really need is studies that judge the impact of drugs not on ‘surrogate’ markers such as HDL levels, but on health.

In recent years, there has been focus on two main types of HDL-raising therapy: niacin (a form of vitamin B3) and what are known as CETP inhibitors. In the current edition of Current Opinions in Cardiology, two papers take a look at the state of the evidence in the area of HDL-raising therapy.

One of these papers comes from researchers based in Manchester, UK [1]. In their paper, the authors acknowledge work which suggests that in those with acceptable LDL levels, low levels of HDL is associated with elevated risk of cardiovascular disease. However, the authors also point out the presence of three recent ‘randomised controlled trials’ which find that neither niacin nor the CETP inhibitor dalcetrapib improved health outcomes. The authors of this paper make the point that, in the future, drugs will be required that actually have benefits for health (and don’t simply raise HDL levels).

The other paper comes from a researcher at the Mayo Clinic in Minnesota in the US [2]. The author of this study reviews, in essence, the same evidence as the authors of the first paper, and draws the same conclusions regarding the benefits (none). The author also draws our attention to the fact that niacin has been found to induce side-effects, and that the CETP inhibitor torcetrapib was found to increase the risk of death.

This review also draws our attention to the fact that two other CETP inhibitors (anacetrapib and evacetrapib) are being trialled but that the results will not be known for some years. Right now, though, given the overall adverse effects seen with HDL-boosting agents to date, I’d say that all bets are off.


1. Schofield JD, et al. High-density lipoprotein cholesterol raising: does it matter? Curr Opin Cardiol. 2013;28(4):464-74

2. Wright RS. Recent clinical trials evaluating benefit of drug therapy for modification of HDL cholesterol. Curr Opin Cardiol. 2013;28(4):389-98

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4 Responses to Two reviews reveal the lack of evidence for HDL-boosting agents

  1. Yossi 14 June 2013 at 9:27 am #

    With reference to your first paragraph, it seems that is not a case of LDL bad, HDL good, but more to do with LDL particle size. The following Youtube video by leading lipidologist Dr Thomas Dayspring, explains this:

  2. Ed Terry 14 June 2013 at 2:45 pm #

    Recent studies using niacin have failed to use an arm that used niacin only. The study that used niacin combined with laropiprant was flawed because the major adverse reactions were caused by laropiprant, not niacin. The major side effects appeared to be a class effect of of PGD2 inhibitors, similar to aspirin.

    Adding niacin to a statin also produced disappointing results.

    The Coronary Drug Project was initially disappointing, finding little benefit from niacin. However, a follow-up study performed years later showed that those in the niacin arm had a lower overall mortality 11 years later.

    Perhaps the biggest challenge with niacin is compliance. The flushing effect is initially problematic and a huge barrier to compliance. Trying to prevent the flushing is almost impossible since the flushing is not caused by the increase in PGD2 only. Niacin also causes the release of serotonin from platelets, which can only be blocked by anti-psychotics.

    Personally, I’ve have great success using niacin and the proper diet. I’ve taken immediate-release niacin for over 10 years. Combined with a diet low in carbohydrates, my coronary calcium score has decreased. Oddly enough, the HDL-raising effects, in terms of percentage increase, is reduced with a low carbohydrate diet. On a high carb diet, the HDL increase was typically 30 to 35%. On a low carb diet, it’s more like 20%.

    Given that every man on my fathers side of the family has suffered either a cerebrovascular or cardiovascular event in their forties, I’m the exception even though I was at greatest risk. I weighed 60 lbs at two years of age, and could (and frequently did) devour a large bag of cookies in a single sitting.

    I acknowledge that taking niacin may not produce any benefits but I’m trying everything I can to reduce my chance at having a heart attack or stroke. It starts with not taking my doctor’s “expert” advice on diet.

  3. michael goroncy 15 June 2013 at 3:01 am #

    Confessions of a lab rat
    In 2005 I joined several thousand others in Pfizer’s CEPT Illuninate study.
    Within a short time 2 things happened!
    (a) my HDL tripled (marvellous) this is what the trial depended on.
    (b) my BP sky-rocketed (mystery) because the side effects were predicted to be marginal and no need for concern)
    Up until then, my BP was ‘bobbing along’ nicely in the 110-120/ 70-80..Although having severe CHD, my BP was excellent and never an issue.

    Now! For the ‘Circus’ part and it’s management.
    My BP shot up to 160-180/ 90/130…not exactly a marginal increase.
    I mentioned this to the Cardiac Research Team who were monitoring Lipids, BP and ECG periodically.
    I told them I know with absolute certainty that I am in the Trial Arm and not the Control Group…They responded with “You don’t know that”.
    Then I dragged my GP (PCP) into the picture and explained this remarkable change in HDL and BP. He was a good, caring GP….and do you know! We spent over a year, adding different Hypertensive drugs and adjusting dosage with no success.

    Meanwhile, I am keeping track of Torcetrapib on the net, and can only hear the ‘crowing’ and excitement of this ‘wonder drug’. The closest I could get to any negative..was that the HDL might in fact be a ‘false reading’ (even though the numbers go up- incidence remains the same).

    As you all know…Pfizer pulled the plug with extreme haste…when only days before, they could ‘smell the money rolling in’. To me, their noble excuse (a pitiful increase in death with the Combo takers) didn’t equate to flushing hundreds of millions down the toilet. And abandoned their search for the holly grail…and never likely to return down that road. And, even though Steven(rent a quote)Nissen came in to deliver an eloquent eulogy…I have some simple questions to put to Pfizer.

    What numbers were they seeing with BP and other markers?
    They ‘shat themselves’ for some reason, and I don’t think we will ever know.

    For my own experience in this trial…is not open to question.
    As for my suspicions…..I stand to be corrected.

  4. Robert Park 15 June 2013 at 10:59 am #

    My sister regularly took part in drug trials during which time she told me that often other participants had side-effects and were removed from the trail the blame being placed on the participants own health conditions yet prior to being selected they were all thoroughly medically examined. The similarity to Michael’s case is interesting.

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