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LIPID CASE 226 Low TC and Low HDL-C Treat? Our first case of 2009 deals with a not uncommon clinical condition on which my opinion is solicited several times a year. It revolves around the ingrained assumption that low HDL-C is always a cardiac nightmare and any human being is doomed unless they have a perfect HDL-C level (whatever that is). A provider contacted me and stated: "I have a simple question. How low can HDL-C be if total cholesterol is less than 150? For example I have a patient with history of CABG with the following lipid profile: TC = 111 HDL-C = 31 TG = 69 LDL-C = 62. Is there a general rule: if total cholesterol is low, how low can HDL-C be before you treat it? I have heard mixed reviews on this and would like it answered by you." DAYSPRING ADVICE: First I am presuming the lipid concentrations reported above are on-treatment lipid levels: likely the patient is on a statin, statin/ezetimibe or statin/niacin combination. We have to be careful with semantics here: A careful reading of the NCEP ATP-III guidelines would reveal the only lipid parameter that guides treatment is LDL-C and the only goals of therapy are LDL-C and non-HDL-C if the TG are elevated > 200 mg/dL. There is no HDL-C or TG level (under 500 mg/dL), per se that mandates treatment and there are no specific HDL-C or TG goals of therapy once treatment begins. NCEP defined several risk categories and stated within each category at what LDL-C level lifestyle and pharmacological therapy is triggered. Once treatment is initiated there are specific LDL-C and non-HDL-C goals of therapy levels, with more aggressive goals in the high and very high risk categories. NCEP states the best way to reduce risk in at risk patients with high TG or low HDL-C is to normalize LDL-C and then non-HDL-C if the TG are high. NCEP mentions that patients with isolated low HDL-C (normal LDL-C, normal TG) who are in A HIGH RISK CATEGORY might be treated with a fibrate or niacin but again offered no specific HDL-C level triggers for such therapy or a specific HDL-C goal of therapy to attain. If you see a person in a lower risk category with low isolated HDL-C, it was not discussed in NCEP. Let's review some of the pathophysiology: In our insulin resistant world, the most common scenario where patients have low HDL-C is in patients with TG/HDL-C disorders (T2DM and metabolic syndromes: full or partial). Yes there is a general rule in Lipidology: As TC drops all cholesterol levels drop. Remember that TC is simply the sum of one's LDL-C, VLDL-C and HDL-C and if cholesterol is leaving the serum those numbers will reduce. The last phase in an HDLs journey in reverse cholesterol transport is to give ups its cholesterol: i.e. the HDL particles delipidates (at the liver or intestine or via CETP) or is endocytosed by the liver Technically speaking, you never ever treat low HDL-C per se, but rather the risk that may be associated with it. In essence you treat any and all of the associated risk factors which are amenable to therapy, presuming they are identified. In untreated insulin resistant patients with low HDL-C, such other treatable risk factors almost always do exist (remnant lipoproteins, cholesterol-poor LDLs). There is no guideline anywhere that tells you to start therapy depending on what the specific HDL-C is. The majority of patients with CAD who have low HDL-C prior to therapy have very high apoB or LDL-P (due to TG induced overproduction of VLDL). Yet, there are genetic conditions where low HDL-C is not associated with CV risk and one would not want to treat those folks unnecessarily (interestingly these people with low HDL-C usually have low apoB levels). As you dramatically lower TC, all cholesterol levels, including HDL-C, will drop. NCEP provides two and only two goals of therapy, both of which are lipid concentration surrogates of apoB (atherogenic particles): LDL-C and non-HDL-C. In the very high risk patient under discussion both have been normalized or in other words that patient has reached his NCEP goals of therapy. This suggests that atherogenic particles no longer exist, so why treat further? You are done with therapy according to guidelines. Also note the TC/HDL-C ratio is perfect despite the low HDL-C and this suggests whatever risk used to be present has disappeared. You might think you want to raise HDL-C to promote reverse cholesterol transport, but readers of my newsletter know a serum HDL-C level has no relationship to the RCT process (see Duffy & Rader. Circulation2006;113:1140-1150). The cholesterol that causes atherosclerosis is trafficked into the artery wall as a component within an apolipoprotein B containing particle: smaller chylomicron and smaller VLDL remnants, IDLs and of course LDL particles (of any size). These particles are driven in by concentration gradients. Once the apo B particle concentrations have been minimized (returned to physiologic levels), they no longer enter the arterial wall. We are still learning what functions HDL particles perform, and believe me we are still in our infancy on this subject. Certainly HDLs can traffic cholesterol from a source of lipidation (usually the liver and small intestine) to its destination for delipidation (steroidogenic tissues, adipose tissue or back to liver or intestine), but many fail to realize that the major component that contributes to the high density of HDLs are the numerous surface proteins (over 50) they traffic. Until we learn the function of each and every one of those proteins we will never truly understand HDLs. Until clinicians can assay the beneficial CV proteins that may or not be present on an HDL we will never totally and accurately predict are we helping a given patient by modulating some laboratory parameter such as how much cholesterol is within all of the HDLs in a deciliter of plasma (HDL-C). The amount of cholesterol within the HDLs has little correlation with the presence or absence of beneficial surface or unbeneficial HDL proteins. The presence or absence of these proteins determines an HDL's functionality: an HDL lacking critical proteins would be "non or dys" functional. I urge you all to read a very recent article entitled HDLs: Fall from grace? in Annals of Medicine 2008; 40: 584-593. The author’s state: the progressive insight that HDL may actually be predominantly a carrier molecule of a wide array of proteins rather than merely a cholesterol-transporter has resulted in the interest to look beyond HDL-C levels alone. Another developing story with HDLs is that it may be more important to know how many HDLs are present (HDL-P) rather than how much cholesterol is inside of the particles (HDL-C). Certainly if one has functional HDLs, it makes sense that having a lot of them would be beneficial and any reduction would be problematic. However even those measurements would not tell us are the HDLs lipidating and delipidating in proper fashion, are they delipidating arterial wall macrophages (macrophage reverse cholesterol transport) and are they carrying the critical proteins. J Am Coll Cardiol 2008;51:634–42. See my writings and slides on the web site www.lipidcenter.com click on professionals and scroll down to PP files and go through the slides on the program called "HDLs Do we have a clue?" It is amazing how many folks try to raise HDL-C when there is no need to do so and where raising it (as in the case at hand) would likely be impossible. In such cases the only way to raise HDL-C would be to raise TC and clearly that would be asinine. Patients who used the Dean Ornish very low fat diet significantly dropped HDL-C yet plaque regressed on angiograms (Lancet. 1990;336:129-133). Of course that same diet significantly dropped apoB. I however would check LDL-P before assuming there are no remaining increases in atherogenic particles (see below). In the patient being discussed: TC = 111 HDL-C = 31 VLDL-C = 53 LDL-C = 62 TG = 69 Non HDL-C = 80 For cholesterol induced atherosclerosis to occur the patient has to have too many apoB particles (which traffic the sterols into the artery). The surrogates in the lipid profile that have some correlations with apoB are TC (if > 200), LDL-C (if > 70 in a very high risk patient) and Non HDL- C (if > 100 in a very high risk patient). Thus all of the apoB-related lipid measurements in this patient are perfect. One could order apoB or LDL-P to be sure and that makes sense to do in a very high risk individual. Bill Cromwell did report in last year's analysis of the Framingham Offspring Study (Journal of Clinical Lipidology 2007;1:83–592) that there are some people with normal LDL-C, normal LDL size and normal TG who still have high LDL-P, because their particles are very cholesterol depleted. If one has cholesterol-depleted LDLs it will take more LDLs to traffic a given level of cholesterol. So if an LDL-P was performed on this man and it was high, further treatment would be indicated to normalize LDL-P. So again if we assume, based on perfect apoB-cholesterol parameters (LDL-C, non-HDL-C) that perfect LDL-P (or apoB) concentrations exist, then why would one want to raise HDL-C? What trial would support that? Why does the Dean Ornish extreme low fat diet so effectively reduce all cholesterol levels? Well the initial substrate from which cholesterol is synthesized is acylCoA (acetoCoA, acetylacetyl CoA) which is derived from fatty acid breakdown (oxidation).

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