Is there a relationship between HDL-C and LDL-C?

Is there a relationship between HDL-C and LDL-C?

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For a gentle introduction to cholesterol and its functions, see a great answer on SE Biology

Whenever I read about how to deal with cholesterol level, the rule is to keep a low LDL fraction, ad a high HDL one.

How to achieve this usually falls into the categories of a healthy body (sport), a healthy diet and possibly medicamentation.

Since generally the advice is more or less the same for both goals (lowering one fraction and increasing the other one), I was wondering if there is a strong relationship between these fractions. In other words - is moving one in the right directions automatically drags the other one (also in the right direction)?

Anecdotally (and this is what triggered my question), I saw my LDL crash almost by 250% (not by chance but through a good diet, etc. - over a few months) and, surprisingly, the HDL go down by 30% as well.

A U-shaped association between the LDL-cholesterol to HDL-cholesterol ratio and all-cause mortality in elderly hypertensive patients: a prospective cohort study

The low-density lipoprotein cholesterol/high-density lipoprotein- cholesterol (LDL-C/HDL-C) ratio is an excellent predictor of cardiovascular disease (CVD). However, previous studies linking the LDL-C/HDL-C ratio to mortality have yielded inconsistent results and been limited by short follow-up periods. Therefore, the aim of the present study was to determine whether the LDL-C/HDL-C ratio could be an effective predictor of all-cause mortality in elderly hypertensive patients.


A total of 6941 hypertensive patients aged 65 years or older who were not treated with lipid-lowering drugs were selected from the Chinese Hypertension Registry for analysis. The endpoint of the study was all-cause mortality. The relationship between the LDL-C/HDL-C ratio and all-cause mortality was determined using multivariate Cox proportional hazards regression, smoothing curve fitting (penalized spline method), subgroup analysis and Kaplan–Meier survival curve analysis.


During a median follow-up of 1.72 years, 157 all-cause deaths occurred. A U-shaped association was found between the LDL-C/HDL-C ratio and all-cause mortality. Patients were divided according to the quintiles of the LDL-C/HDL-C ratio. Compared to the reference group (Q3: 1.67–2.10), patients with both lower (Q1 and Q2) and higher (Q4 and Q5) LDL-C/HDL-C ratios had higher all-cause mortality (< 1.67: HR 1.81, 95% CI: 1.08–3.03 ≥2.10: HR 2.00, 95% CI: 1.18–3.39). Compared with the lower and higher LDL-C/HDL-C ratio groups, patients with LDL-C/HDL-C ratios of 1.67–2.10 had a significantly higher survival probability (log-rank P = 0.038).


The results suggest that there is a U-shaped association between the LDL-C/HDL-C ratio and all-cause mortality. Both lower and higher LDL-C/HDL-C ratios were associated with increased all-cause mortality in elderly hypertensive patients.

Raised cholesterol level itself is not the problem. But, it indicates there is a problem somewhere such as inflammation, infection, etc. The cholesterol level raises to heal the inflammation, eradicate infection, remove toxins, etc.

Lipid panel test is the most used test. It is useful for the assessment of different lipids in the blood. It provides total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides levels.

Here we are trying to provide healthy ranges of Total cholesterol, HDL-C, LDL-C, and triglyceride. This individual range does not provide useful information. But, you can calculate TG/HDL-C ratio and Non-HDL-C to make it useful.

Total cholesterol healthy & unhealthy range

Total cholesterol level is the sum of all lipids in your blood lipoproteins (VLDL, LDL, and HDL). TC = LDL-C + HDL-C + VLDL-C

  1. Normal TC: Less than 200 mg/dL (< 5.2 mmol/l)
  2. Borderline TC: 200 to 239 mg/dL (5.3 to 6.2 mmol/l)
  3. High TC: More than 239 mg/dL (> 6.2 mmol.l)

LDL-C healthy & unhealthy range

Low-density lipoproteins (LDL) cholesterol is considering as bad cholesterol, but not exactly. Previously LDL is considering to promotes plaque formation and thus increases heart disease risk. The healthy LDL-C ranges are as below.

  1. Normal LDL: Less than 130 mg/dL (< 3.36 mmol/l)
  2. Borderline LDL: 130 to 159 mg/dL (3.36 to 4.11 mmol/l)
  3. High LDL: More than 159 mg/dL (> 4.11 mmol.l)

Most labs estimate the concentration of low-density lipoprotein cholesterol using Friedewald formula (not ultracentrifuge). This indirect LDL cholesterol estimation is unreliable, when the triglyceride is high or low.

Friedewald formula is useful to calculate LDL cholesterol. LDL-C = TC – HDL-C - TG/5

HDL-C healthy & unhealthy range

High-density lipoproteins (HDL) cholesterol is considering as good cholesterol, but not exactly. Previously HDL is considering to decreases plaque formation. Thus, it may lower heart disease risk it is partly correct. The healthy HDL-C ranges are as below.

  • Normal HDL: More than 60 mg/dL (> 1.55 mmol/l)
  • Borderline HDL: 40 to 60 mg/dL (1.03 to 1.55 mmol/l)
  • High HDL: Less than 40 mg/dL (< 1.03 mmol.l)

Labs measures HDL cholesterol by separating other lipoprotein fractions. High-density lipoprotein cholesterol (HDL-C) is the cholesterol in HDL particles contain.

Triglycerides healthy & unhealthy range

Triglycerides are the fats found in your blood, which are the major source of energy.

  • Normal Triglycerides: Less than 150 mg/dL (< 1.69 mmol/l)
  • Borderline Triglycerides: 150 to 199 mg/dL (1.69 to 2.25 mmol/l)
  • High Triglycerides: More than 199 mg/dL (> 2.25 mmol.l)

If you have high cholesterol and heart disease risk, then you may need medication. Various treatment options for high cholesterol are dietary, lifestyle changes and medicines.

Many alternative treatments also available, they are herbal, homeopathy, yoga, acupressure, and reflexology.

VLDL level calculated by dividing the triglyceride level by five. You can reduce triglyceride by exercise and consume omega-3 fatty acids. Some sources of omega-3 are fish, flax seed oil, walnut, etc. Important, you can lower triglyceride by cutting down carbohydrate intakes (switch to low-carb diet).

TG to HDL-C ratio

TG/HDL-C ratio should maintain below 3.8. Otherwise, increases your chance for small dense LDL phenotype B.

  • Normal: Less than 3.5 (in Men) < 3.0 (in Women)
  • Moderate: 3.5 to 5.0 (in Men) 3.0 to 4.4 (in Women)
  • High: More than 5.0 (in Men) > 4.4 (in Women)


Non-HDL-C is equal to total cholesterol minus HDL-C i.e. Non-HDL-C = TC – HDL-C.

  • Normal: Less than 130 mg/dL (< 3.3 mmol/l)
  • Borderline: 130 to 159 mg/dL (3.3 to 4.1 mmol/l)
  • High: More than 159 mg/dL (> 4.1 mmol.l)

Non-HDL-C is a better predictor of future CVD risk than LDL-C.

Why it Was Not Worth the Wait

Eliminating treatment targets: A paradigm shift
The new guideline has caused much controversy by changing the fundamentals of cholesterol treatment from an approach that treats to specific LDL-C and non-HDL-C targets to one that treats specific patient populations regardless of their lipid profile. It encourages repeating a lipid panel 4-12 weeks after the initiation of statin therapy to assess patient compliance rather than the efficacy of statin therapy. It presumes that high-intensity statin therapy reduces LDL-C by &ge 50% while moderate-intensity reduces it by 30% to < 50%. However, this reduction is not a universal finding in all studies because multiple factors are involved in determining each individual's response to statin therapy.

For example, in ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden), 4 secondary prevention patients on high-intensity rosuvastatin therapy of 40 mg daily had a mean LDL-C reduction of 53% only thus, approximately half of the patients did not meet the definition of high-intensity statin therapy in the new guideline. The casual role of LDL-C in the pathophysiology of ASCVD and the totality of evidence from RCTs and other studies point towards one core concept the lower the LDL-C, the less the ASCVD risk. As pointed out by Raymond et al, 5 there is a reproducible relationship between the LDL-C level achieved and the absolute risk in primary and secondary prevention populations (Slide 1). Therefore, we believe that having LDL-C or non-HDL-C treatment targets is crucial in assessing and treating residual risk at follow up after initiating statin therapy.

Limited role for non-statin lipid lowering medications
The new guideline makes it clear that statins are a must, but fails to acknowledge what to do when statins are not enough or when patients are intolerant to statins. It does not strongly recommend the use of non-statin lipid lowering medications because of the lack of definitive data that proves its efficacy. A recent systematic review showed that the combination of a lower dose statin and another lipid-lowering medication is more effective at lowering LDL-C than a high dose statin alone. 6 There is no doubt about the efficacy of high-intensity statins as first-line therapy in high-risk patient however, the role of non-statin medications in reducing residual risk and in patients with statin intolerance is minimized in the new guidelines. Non-statin lipid lowering medications are very effective at lowering LDL-C and most experts would add one or more when the LDL-C level remains elevated or when patients have recurrent ASCVD despite high dose statin therapy.

The new 10-year ASCVD risk calculator
Perhaps the most controversial aspect of the new guideline is the new risk calculator. The same guideline that eliminates treatment goals due to the lack of RCT data to support it, recommends using a calculator that was neither extensively validated in primary prevention populations nor released early for public commentary and expert opinion. It was derived from five population-based cohorts of African Americans and non-Hispanic whites and relies heavily on age and sex to determine ASCVD risk while ignoring other important factors such as family history. 2

Soon after the release of the new guideline, Drs. Ridker and Cook showed that when the new calculator was applied to more recent cohorts such as the Women's Health Study, Physician's Health Study and Women's Health Initiative, it overestimated the 10-year ASCVD risk by 75% to 150% making approximately 30 million more Americans eligible for statin treatment. 7

A recent study in a Swiss population showed the new risk calculator doubled the prevalence of high-risk individuals compared to the European Society of Cardiology SCORE equation. 8 It led to a 30-fold increase in the number of high-risk individuals amongst those 50-60 years old and a total extra cost of treatment of 333.7 million Euros per year. Moreover, the new calculator makes virtually all African American men older than 62 years old with no other risk factors candidates for at least a moderate intensity statin (Slide 2). Given its inconsistent performance in different populations, we would have expected extensive validation of the efficacy of this calculator in large prospective studies before its release.

Primary prevention and the unfortunate young
The new guideline recommendations for using statins in primary prevention are limited to patients 40-75 years old unless their LDL-C is &ge 190 mg/dL. However, the process of atherosclerosis starts at very young age and therefore failure to start lipid-lowering medications in the younger dyslipidemic population is a failure of primary prevention (Slide 3). Despite the absence of RCTs that address statin therapy in the young age group, a moderate or high dose statin may be considered in certain high-risk individuals.

What happened to hypertriglyceridemia?
Hypertriglyceridemia is a marker of dyslipidemia. In the current era of diabetes, obesity and metabolic syndrome epidemics, we have witnessed increasing prevalence of elevated triglyceride-rich remnant lipoproteins, characteristic of insulin resistance. These include very-low density lipoproteins, intermediate-density lipoproteins, and chylomicron remnant particles that may be more atherogenic than LDL-C. 9 Therefore, hypertriglyceridemia may be a potential indication to assess residual risk by measuring more inclusive measures of atherogenic cholesterol such as non-HDL-C or apoB and possibly initiate statins.


The new guideline document, with all its pros and cons, represents a colossal shift in cholesterol treatment. In the midst of all this controversy, we believe we can find common ground where we all can agree on certain core concepts. We can all agree that treatment with a moderate to high-intensity statin is a must for all patients within the four major groups identified by the guideline. We can also agree that LDL-C and non-HDL-C treatment targets are crucial for residual risk assessment and treatment. Non-statin lipid lowering medications may be beneficial for reducing residual risk and for statin intolerant patients. The new calculator should be validated extensively in more cohorts and needs to include other factors such as family history. Physicians and patients must engage in a healthy dialogue about the benefits and risks of treatment with statins as well as non-statins. In conclusion, we should always remember that patients are unique and guidelines are only a tool for direction not for dictating clinical practice.

  1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002106:3143&ndash3421.
  2. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013. [Epub Ahead of Print].
  3. Graham R, Mancher M, Wolman DM, Greenfield S, SteinberE, eds Institute of Medicine. Clinical Practice Guidelines We Can Trust. Washington, DC Nat Acad Proc 2011:253.
  4. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006295:1556&ndash1565.
  5. Raymond C, Cho L, Rocco M, Hazen SL. New cholesterol guidelines: worth the wait? Cleve Clin J Med 201481:11&ndash19.
  6. Gudzune KA, Monroe AK, Sharma R, Ranasinghe PD, Chelladurai Y, Robinson KA. Effectiveness of Combination Therapy With Statin and Another Lipid-Modifying Agent Compared With Intensified Statin Monotherapy: A Systematic Review. Ann Intern Med 2014. [Epub ahead of print]
  7. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013382:1762&ndash1765.
  8. Vaucher J, Marques-Vidal P, Preisig M, Waeber G, Vollenweider P. Population and economic impact of the 2013 ACC/AHA guidelines compared with European guidelines to prevent cardiovascular disease. Eur Heart J 2014. [Epub ahead of print]
  9. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 201361:427&ndash436.

Keywords: Cholesterol, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Risk Reduction Behavior

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In: Journal of Lipid Research , Vol. 51, No. 6, 01.06.2010, p. 1546-1553.

Research output : Contribution to journal › Article › Research › peer-review

T1 - Effect of statins on HDL-C

T2 - A complex process unrelated to changes in LDL-C: Analysis of the VOYAGER database

AU - Brandrup-Wognsen, Gunnar

N2 - The relationship between statin-induced increases in HDL cholesterol (HDL-C) concentration and statin-induced decreases in LDL cholesterol (LDL-C) is unknown. The effects of different statins on HDL-C levels, relationships between changes in HDL-C and changes in LDL-C, and predictors of statin-induced increases in HDL-C have been investigated in an individual patient meta-analysis of 32,258 dyslipidemic patients included in 37 randomized studies using rosuvastatin, atorvastatin, and simvastatin. The HDL-C raising ability of rosuvastatin, and simvastatin was comparable, with both being superior to atorvastatin. Increases in HDL-C were positively related to statin dose with rosuvastatin and simvastatin but inversely related to dose with atorvastatin. There was no apparent relationship between reduction in LDL-C and increase in HDL-C, whether analyzed overall for all statins (correlation coeffi-cient = 0.005) or for each statin individually. Percentage increase in apolipoprotein A-I was virtually identical to that of HDL-C at all doses of the three statins. Baseline concentrations of HDL-C and triglyceride (TG) and presence of diabetes were strong, independent predictors of statin-induced elevations of HDL-C. Statins vary in their HDL-C raising ability. The HDL-C increase achieved by all three statins was independent of LDL-C decrease. However, baseline HDL-C and TGs and the presence of diabetes were predictors of statin-induced increases in HDL-C.

AB - The relationship between statin-induced increases in HDL cholesterol (HDL-C) concentration and statin-induced decreases in LDL cholesterol (LDL-C) is unknown. The effects of different statins on HDL-C levels, relationships between changes in HDL-C and changes in LDL-C, and predictors of statin-induced increases in HDL-C have been investigated in an individual patient meta-analysis of 32,258 dyslipidemic patients included in 37 randomized studies using rosuvastatin, atorvastatin, and simvastatin. The HDL-C raising ability of rosuvastatin, and simvastatin was comparable, with both being superior to atorvastatin. Increases in HDL-C were positively related to statin dose with rosuvastatin and simvastatin but inversely related to dose with atorvastatin. There was no apparent relationship between reduction in LDL-C and increase in HDL-C, whether analyzed overall for all statins (correlation coeffi-cient = 0.005) or for each statin individually. Percentage increase in apolipoprotein A-I was virtually identical to that of HDL-C at all doses of the three statins. Baseline concentrations of HDL-C and triglyceride (TG) and presence of diabetes were strong, independent predictors of statin-induced elevations of HDL-C. Statins vary in their HDL-C raising ability. The HDL-C increase achieved by all three statins was independent of LDL-C decrease. However, baseline HDL-C and TGs and the presence of diabetes were predictors of statin-induced increases in HDL-C.

The straight dope on cholesterol – Part VII

Read Time 15 minutes

Want to catch up with other articles from this series?

Previously, in Part I, Part II, Part III, Part IV, Part V ,and Part VI of this series, we addressed these 8 concepts:

#1What is cholesterol?

#2What is the relationship between the cholesterol we eat and the cholesterol in our body?

#3Is cholesterol bad?

#4How does cholesterol move around our body?

#5 How do we measure cholesterol?

#6How does cholesterol actually cause problems?

#7Does the size of an LDL particle matter?

#8Why is it necessary to measure LDL-P, instead of just LDL-C?

(No so) Quick refresher on take-away points from previous posts, should you need it:

  1. Cholesterol is “just” another fancy organic molecule in our body but with an interesting distinction: we eat it, we make it, we store it, and we excrete it – all in different amounts.
  2. The pool of cholesterol in our body is essential for life. No cholesterol = no life.
  3. Cholesterol exists in 2 formsunesterified or “free” (UC) and esterified (CE) – and the form determines if we can absorb it or not, or store it or not (among other things).
  4. Much of the cholesterol we eat is in the form of CE. It is not absorbed and is excreted by our gut (i.e., leaves our body in stool). The reason this occurs is that CE not only has to be de-esterified, but it competes for absorption with the vastly larger amounts of UC supplied by the biliary route.
  5. Re-absorption of the cholesterol we synthesize in our body (i.e., endogenous produced cholesterol) is the dominant source of the cholesterol in our body. That is, most of the cholesterol in our body was made by our body.
  6. The process of regulating cholesterol is very complex and multifaceted with multiple layers of control. I’ve only touched on the absorption side, but the synthesis side is also complex and highly regulated. You will discover that synthesis and absorption are very interrelated.
  7. Eating cholesterol has very little impact on the cholesterol levels in your body. This is a fact, not my opinion. Anyone who tells you different is, at best, ignorant of this topic. At worst, they are a deliberate charlatan. Years ago the Canadian Guidelines removed the limitation of dietary cholesterol. The rest of the world, especially the United States, needs to catch up. To see an important reference on this topic, please look here.
  8. Cholesterol and triglycerides are not soluble in plasma (i.e., they can’t dissolve in water) and are therefore said to be hydrophobic.
  9. To be carried anywhere in our body, say from your liver to your coronary artery, they need to be carried by a special protein-wrapped transport vessel called a lipoprotein.
  10. As these “ships” called lipoproteins leave the liver they undergo a process of maturation where they shed much of their triglyceride “cargo” in the form of free fatty acid, and doing so makes them smaller and richer in cholesterol.
  11. Special proteins, apoproteins, play an important role in moving lipoproteins around the body and facilitating their interactions with other cells. The most important of these are the apoB class, residing on VLDL, IDL, and LDL particles, and the apoA-I class, residing for the most part on the HDL particles.
  12. Cholesterol transport in plasma occurs in both directions, from the liver and small intestine towards the periphery and back to the liver and small intestine (the “gut”).
  13. The major function of the apoB-containing particles is to traffic energy (triglycerides) to muscles and phospholipids to all cells. Their cholesterol is trafficked back to the liver. The apoA-I containing particles traffic cholesterol to steroidogenic tissues, adipocytes (a storage organ for cholesterol ester) and ultimately back to the liver, gut, or steroidogenic tissue.
  14. All lipoproteins are part of the human lipid transportation system and work harmoniously together to efficiently traffic lipids. As you are probably starting to appreciate, the trafficking pattern is highly complex and the lipoproteins constantly exchange their core and surface lipids.
  15. The measurement of cholesterol has undergone a dramatic evolution over the past 70 years with technology at the heart of the advance.
  16. Currently, most people in the United States (and the world for that matter) undergo a “standard” lipid panel, which only directly measures TC, TG, and HDL-C. LDL-C is measured or most often estimated.
  17. More advanced cholesterol measuring tests do exist to directly measure LDL-C (though none are standardized), along with the cholesterol content of other lipoproteins (e.g., VLDL, IDL) or lipoprotein subparticles.
  18. The most frequently used and guideline-recommended test that can count the number of LDL particles is either apolipoprotein B or LDL-P NMR, which is part of the NMR LipoProfile. NMR can also measure the size of LDL and other lipoprotein particles, which is valuable for predicting insulin resistance in drug naïve patients, before changes are noted in glucose or insulin levels.
  19. The progression from a completely normal artery to a “clogged” or atherosclerotic one follows a very clear path: an apoB containing particle gets past the endothelial layer into the subendothelial space, the particle and its cholesterol content is retained, immune cells arrive, an inflammatory response ensues “fixing” the apoB containing particles in place AND making more space for more of them.
  20. While inflammation plays a key role in this process, it’s the penetration of the endothelium and retention within the endothelium that drive the process.
  21. The most common apoB containing lipoprotein in this process is certainly the LDL particle. However, Lp(a) and apoB containing lipoproteins play a role also, especially in the insulin resistant person.
  22. If you want to stop atherosclerosis, you must lower the LDL particle number. Period.
  23. At first glance it would seem that patients with smaller LDL particles are at greater risk for atherosclerosis than patients with large LDL particles, all things equal.
  24. “A particle is a particle is a particle.” If you don’t know the number, you don’t know the risk.
  25. With respect to laboratory medicine, two markers that have a high correlation with a given outcome are concordant – they equally predict the same outcome. However, when the two tests do not correlate with each other they are said to be discordant.
  26. LDL-P (or apoB) is the best predictor of adverse cardiac events, which has been documented repeatedly in every major cardiovascular risk study.
  27. LDL-C is only a good predictor of adverse cardiac events when it is concordant with LDL-P otherwise it is a poor predictor of risk.
  28. There is no way of determining which individual patient may have discordant LDL-C and LDL-P without measuring both markers.
  29. Discordance between LDL-C and LDL-P is even greater in populations with metabolic syndrome, including patients with diabetes. Given the ubiquity of these conditions in the U.S. population, and the special risk such patients carry for cardiovascular disease, it is difficult to justify use of LDL-C, HDL-C, and TG alone for risk stratification in all but the most select patients.
  30. To address this question, however, one must look at changes in cardiovascular events or direct markers of atherosclerosis (e.g., IMT) while holding LDL-P constant and then again holding LDL size constant. Only when you do this can you see that the relationship between size and event vanishes. The only thing that matters is the number of LDL particles – large, small, or mixed.

Concept #9 – Does “HDL” matter after all?

Last week was the largest annual meeting of the National Lipid Association (NLA) in Phoenix, AZ. The timing of the meeting could not have been better, given the huge buzz going around on the topic of “HDL.” (If you’re wondering why I’m putting HDL in quotes, I’ll address it shortly.)

What buzz, you ask? Many folks, including our beloved health columnists at The New York Times, are talking about the death of the HDL hypothesis – namely, the notion that HDL is the “good cholesterol.”

Technically, this “buzz” started about 6 years ago when Pfizer made headlines with a drug in their pipeline called torcetrapib. Torcetrapib was one of the most eagerly anticipated drugs ever, certainly in my lifetime, as it had been shown to significantly raise plasma levels of HDL-C. You’ll recall from part II of this series, HDL particles play an important role in carrying cholesterol from the subendothelial space back to the liver via a process called reverse cholesterol transport (RCT). Furthermore, many studies and epidemiologic analyses have shown that people with high plasma levels of HDL-C have a lower incidence of coronary artery disease.

In the case of torcetrapib, there was an even more compelling reason to be optimistic. Torcetrapib blocked the protein cholesterylester transfer protein, or CETP, which facilitates the collection and one-to-one exchange of triglycerides and cholesterol esters between lipoproteins. Most (but not all) people with a mutation or dysfunction of this protein were known to have high levels of HDL-C and lower risk of heart disease. Optimism was very high that a drug like torcetrapib, which could mimic this effect and create a state of more HDL-C and less LDL-C, would be the biggest blockbuster drug ever.

The past month or so has seen this discussion intensify, which I’ll quickly try to cover below.

The data


After several smaller clinical trials showed that patients taking torcetrapib experienced both an increase in HDL-C and a reduction in LDL-C, a large clinical trial pitting atorvastatin (Lipitor) against atorvastatin + torcetrapib was underway. This trial was to be the jewel in the crown of Pfizer. It was already known that Lipitor reduced coronary artery disease (and reduced LDL-C, though this may have been a bystander effect and real reduction in mortality may be better attributed to the reduction in LDL-P).

I still remember exactly where I was standing, on the corner of Kerney St. and California St. in the heart of San Francisco’s financial district, on that December day back in 2006 when it was announced the trial had been halted because of increased mortality in the group receiving torcetrapib. In other words, adding torcetrapib actually made things worse. I was shocked.

Many reasons were offered for this, including the notion that torcetrapib was, indeed, helpful, but because of unanticipated side-effects, (raising blood pressure in some patients and altering electrolyte balance in others), the net impact was harmful. Some even suggested that the drug could be useful in the “right” patients (e.g., those with low HDL-C, but normal blood pressure). Furthermore, in two subsequent studies looking at carotid IMT (thickening of the carotid arteries) and intravascular ultrasound, there was no reduction in atherosclerosis.

This was a big strike against the HDL hypothesis and work on torcetrapib was immediately halted.

Niacin has long been known to raise HDL-C and has actually been used therapeutically for this reason for many years. The AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides – you can’t have trials in medicine without catchy names!) sought to test this. The trial randomly assigned over 3,000 patients with known and persistent, but stable and well treated cardiovascular risk, to one of two treatments:

  1. Simvastatin (40-80 mg/day), +/- ezetimibe (10 mg/day) as necessary to maintain LDL-C below 70 mg/dL + placebo (a tiny dose of crystalline niacin to cause flushing)
  2. As above, but instead of a placebo, patients were given 1,500 to 2,000 mg/day of extended-release niacin.

Both arms of the study had their LDL-C < 70 mg/dL, non-HDL-C < 100 md/dL and apoB < 80 mg/dL, but despite the statin or statin + ezetimibe treatment still had low HDL-C. So, if niacin raised HDL-C and reduced events, the HDL raising hypothesis would be proven.

Simvastatin, as its name suggests, is a statin which primarily works by blocking HMG-CoA reductuse, an enzyme necessary to synthesize endogenous cholesterol. Ezetimibe works on the other end of problem, by blocking the NPC1L1 transporter on gut enterocytes and hepatocytes at the hepatobiliary junction (for a quick refresher, go back to part I of this series and look at the second figure – ezetimibe blocks the “ticket taker” in the bar).

After two years the niacin group, as expected, had experienced a significant increase in plasma HDL-C (along with some other benefits like a greater reduction in plasma triglycerides). However, there was no improvement in patient survival. The trial was futile and the data and safety board halted the trial. In other words, for patients with cardiac risk and LDL-C levels at goal with medication niacin, despite raising HDL-C and lowering TG, did nothing to improve survival. This was another strike against the HDL hypothesis.


By 2008, as the AIM-HIGH trial was well under way, another pharma giant, Roche, was well into clinical trials with another drug that blocked CETP. This drug, a cousin of torcetrapib called dalcetrapib, albeit a weaker CETP-inhibitor, appeared to do all the “right” stuff (i.e., it increased HDL-C) without the “wrong” stuff (i.e., it did not appear to adversely affect blood pressure). It did nothing to LDL-C or apoB.

This study, called dal-OUTCOMES, was similar to the other trials in that patients were randomized to either standard of care plus placebo or standard of care plus escalating doses of dalcetrapib. A report of smaller safety studies (called dal-Vessel and Dal-Plaque) was published a few months ago in the American Heart Journal, and shortly after Roche halted the phase 3 clinical trial. Once again, patients on the treatment arm did experience a significant increase in HDL-C, but failed to appreciate any clinical benefit. Another futile trial.

Currently, two additional CETP inhibitors, evacetrapib (manufactured by Lilly) and anacetrapib (manufactured by Merck) are being evaluated. They are much more potent CETP inhibitors and, unlike dalcetrapib, also reduce apoB and LDL-C and Lp(a). Both Lilly and Merck are very optimistic that their variants will be successful where Pfizer’s and Roche’s were not, for a number of reasons including greater anti-CETP potency.

Nevertheless, this was yet another strike against the HDL hypothesis because the drug only raised HDL-C and did nothing to apoB. If simply raising HDL-C without attacking apoB is a viable therapeutic strategy, the trial should have worked. We have been told for years (by erroneous extrapolation from epidemiologic data) that a 1% rise in HDL-C would translate into a 3% reduction in coronary artery disease. These trials would suggest otherwise.

Mendelian randomization

On May 17 of this year a large group in Europe (hence the spelling of randomization) published a paper in The Lancet, titled, “Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.” Mendelian randomization, as its name sort of suggests, is a method of using known genetic differences in large populations to try to “sort out” large pools of epidemiologic data.

In the case of this study, pooled data from tens of studies where patients were known to have myocardial infarction (heart attacks) were mapped against known genetic alterations called SNPs (single nucleotide polymorphisms, pronounced “snips”). I’m not going to go into detail about the methodology because it would take 3 more blog posts., But, the reason for doing this analysis was to ferret out if having a high HDL-C was (only) correlated with better cardiovascular outcome, which has been the classic teaching, or if there was any causal relationship. In other words, does having a high HDL-C cause you to have a lower risk of heart disease or is it a marker for something else?

This study found, consistent with the trials I’ve discussed above, that any genetic polymorphism that seems to raise HDL-C does not seem to protect from heart disease. That is, patients with higher HDL-C due to a known genetic alteration did not seem to have protection from heart disease as a result of that gene. This suggests that people with high or low HDL-C who get coronary artery disease may well have something else at play.

Oh boy. This seems like the last nail in the casket of the entire “HDL” hypothesis, as evidenced by all of the front page stories worldwide.

The rub: the difference between HDL-C and HDL-P

The reason I’ve been referring to high density lipoprotein as “HDL,” unless specifically referring to HDL-C, is that HDL-P and HDL-C are not the same thing. Just as you are now intimately familiar with the notion that LDL-C and LDL-P are not the same thing, the same is true for “HDL” which simply stands for high density lipoprotein, and like LDL is not a lab assay. In fact, unpublished data from the MESA trial found that the correlation between HDL-C and HDL-P was only 0.73, which is far from “good enough” to say HDL-C is a perfect proxy for HDL-P.

HDL-C, measured in mg/dL (or mmol/L outside of the U.S.), is the mass of cholesterol carried by HDL particles in a specified volume (typically measured as X mg of cholesterol per dL of plasma). HDL-P is something entirely different. It’s the number of HDL particles (minus unlipidated apoA-I and prebeta-HDLs: at most 5% of HDL particles) contained in a specified volume (typically measured as Y micromole of particles per liter).

As you can see in the figure below (courtesy of Jim Otvos’ presentation at the NLA meeting 2 weeks ago), the larger an HDL particle, the more cholesterol it carries. So, an equal number of large versus small HDL particles (equal HDL-P) can carry very different amounts of cholesterol (different HDL-C). Of course, it’s never this simple because HDL particles, like their LDL counterparts, don’t just carry cholesterol. They carry triglycerides, too. Keep in mind, HDL core CE/TG ratio is about 10:1 or greater – if the large HDL carries TG, it will not be carrying very much cholesterol.

So, the important point is that HDL-C is not the same as HDL-P (which is also not the same as apoAI, as HDL particles can carry more than one apoAI).

But there’s something else going on here. If you look at the figure below, from the Framingham cohort, you’ll note something interesting. As HDL-C rises, it does so not in a uniform or “across the board” fashion. A rise in HDL-C seems to disproportionately result from an increase in large HDL particles. In other words, as HDL-C rises, it doesn’t necessarily mean HDL-P is rising at all, and certainly not as much.

As you can see, for increases in HDL-C at low levels (i.e., below 40 mg/dL) the increase in small particles seems to account for much of the increase in total HDL-P, While for increases over 40 mg/dL, the increase in large particles seems to account for the increase in HDL-C. Also note that as HDL-C rises above 45 mg/dL, there is almost no further increase in total HDL-P – the rise in HDL-C is driven by enlargement of the HDL particle – more cholesterol per particle – not the drop in small HDL-P. This reveals to us that the small HDL particles are being lipidated.

Is there a reason to favor small HDL particles over large ones?

In the 2011 article, “Biological activities of HDL subpopulations and their relevance to cardiovascular disease,” published in Trends in Molecular Medicine, the authors describe in great detail some of protective mechanisms imparted by HDL particles.

Large HDL particles may be less protective and even dysfunctional in certain pathological states, whereas small to medium-sized HDL particles seem to confer greater protection through the following mechanisms:

  • Greater antioxidant activity
  • Greater anti-inflammatory activity
  • Greater cholesterol efflux capacity
  • Greater anti-thrombotic properties

In other words, particle for particle, it seems a small HDL particle may be better at transporting cholesterol from the subendothelial space (technically, they acquire cholesterol from cholesterol-laden macrophages or foam cells in the subedothelial space) elsewhere, better at reducing inflammation, better at preventing clotting, and better at mitigating the problems caused by oxidative free radicals.

Of course, reality is complicated. If there was no maturation from small to large HDL particles (i.e., the dynamic remodeling of HDL), the system would be faulty. So, the truth is that all HDL sizes are required and that HDL particles are in a constant dynamic state (or “flux”) of lipidating and delipidating, and the real truth is no particular HDL size can be said to be the best. If the little HDLs do not enlarge, the ApoA-I mediated lipid trafficking system is broken.

The truth about the old (and overly simplistic) term called reverse cholesterol transport (RCT)

HDL particles traffic cholesterol and proteins and last in plasma on average for 5 days. They are in a constant state of acquiring cholesterol (lipidation) and delivering cholesterol (delipidation). There are membrane receptors on cells that can export cholesterol to HDL particles (sterol efflux transporters) or extract cholesterol or cholesterol ester from HDL particles (sterol influx transporters).

The vast majority of lipidation occurs (in order): 1) at the liver, 2) the small intestine, 3) adipocytes and 4) peripheral cells, including plaque if present. The liver and intestine account for 95% of this process. The amount of cholesterol pulled out of arteries (called macrophage reverse cholesterol transport) is critical to disease prevention but is so small it has no effect on serum HDL levels. Even in patients with extensive plaque, the cholesterol in that plaque is about 0.5% of total body cholesterol. HDL particles circulate for several days as a ready reserve of cholesterol: almost no cell in humans require a delivery of cholesterol as cells synthesize all they need. However, steroidogenic hormone producing tissues (e.g., adrenal cortex and gonads) do require cholesterol and the HDL particle is the primary delivery truck.

If, as is the case in a medical emergency, the adrenal gland must rapidly make a lot of cortisone, the HDL particles are there with the needed cholesterol. This explains the low HDL-C typically seen in patients with severe infections (e.g., sepsis) and severe inflammatory conditions (e.g., Rheumatoid Arthritis).

Sooner or later HDL particles must be delipidated, and this takes place at: 1) the adrenal cortex or gonads 2) the liver, 3) adipocytes, 4) the small intestine (TICE or transintestinal cholesterol efflux) or give its cholesterol to an apoB particle (90% of which are LDLs) to return to the liver. A HDL particle delivering cholesterol to the liver or intestine is called direct reverse cholesterol transport (RCT), whereas a HDL particle transferring its cholesterol to an apoB particle which returns it to the liver is indirect RCT. Hence, total RCT = direct RCT + indirect RCT.

The punch line: a serum HDL-C level has no known relationship to this complex process of RCT. The last thing a HDL does is lose its cholesterol. The old concept that a drug or lifestyle that raises HDL-C is improving the RCT process is wrong it may or may not be affecting that dynamic process. Instead of calling this RCT, it would be more appropriately called apoA-I trafficking of cholesterol.

Why do drugs that specifically raise HDL-C seem to be of little value?

As I’ve argued before, while statins are efficacious at preventing heart disease, it’s sort of by “luck” as far as most prescribing physicians are concerned. Most doctors use cholesterol lowing medication to lower LDL-C, not LDL-P. Since there is an overlap (i.e., since the levels of LDL-P and LDL-C are concordant) in many patients, this misplaced use of statins seems to work “ok.” I, and many others far more knowledgeable, would argue that if statins and other drugs were used to lower LDL-P (and apoB), instead of LDL-C, their efficacy would be even greater. The same is true for dietary intervention.

Interestingly, (and I would have never known this had Jim Otvos not graciously spent a hour on the phone with me two weeks ago giving me a nuanced HDL tutorial), a study that went completely unnoticed by the press in 2010, published in Circulation, actually did a similar analysis to the Lancet paper, except that the authors looked at HDL-P instead of HDL-C as the biomarker and looked at the impact of phospholipid transfer protein (PLTP) on HDL metabolism. In this study, though not the explicit goal, the authors found that an increase in the number of HDL particles and smaller HDL particles decreased the risk of cardiovascular disease. The key point, of course, is that the total number of HDL particles rose, and it was driven by increased small HDL-P. The exact same thing was seen in the VA-HIT trial: the cardiovascular benefit of the treatment (fibrate) was related to the rise in total HDL-P which was driven by the fibrates’ ability to raise small HDL-P.

It seems the problem with the “HDL hypothesis” is that it’s using the wrong marker of HDL. By looking at HDL-C instead of HDL-P, these investigators may have missed the point. Just like LDL, it’s all about the particles.


  1. HDL-C and HDL-P are not measuring the same thing, just as LDL-C and LDL-P are not.
  2. Secondary to the total HDL-P, all things equal it seems smaller HDL particles are more protective than large ones.
  3. As HDL-C levels rise, most often it is driven by a disproportionate rise in HDL size, not HDL-P.
  4. In the trials which were designed to prove that a drug that raised HDL-C would provide a reduction in cardiovascular events, no benefit occurred: estrogen studies (HERS, WHI), fibrate studies (FIELD, ACCORD), niacin studies, and CETP inhibition studies (dalcetrapib and torcetrapib). But, this says nothing of what happens when you raise HDL-P.
  5. Don’t believe the hype: HDL is important, and more HDL particles are better than few. But, raising HDL-C with a drug isn’t going to fix the problem. Making this even more complex is that HDL functionality is likely as important, or even more important, than HDL-P, but no such tests exist to “measure” this.

Two apolipoprotein A1 chains (magenta ribbons) complexed with cholesterol (orange balls) and phospholipids, after PDB 3K2S by Ayacop [Public domain], via Wikimedia Commons

High-density lipoprotein cholesterol and risk of cardiovascular disease

Unlike low-density lipoprotein (LDL) cholesterol, the causality of high-density lipoprotein (HDL) in the development of atherosclerotic cardiovascular disease remains controversial. Prior observational studies have suggested a graded, inverse relationship between HDL cholesterol and both cardiovascular disease and total mortality, so that higher HDL is better. However, recent large-scale cohort studies and Mendelian randomisation trials have failed to confirm that higher HDL levels are associated with improved outcomes. Indeed, there are some reports of increased cardiovascular events and even increased mortality associated with very high levels of HDL. In addition, pharmaceutical intervention studies aimed at increasing HDL levels did not result in amelioration of cardiovascular outcomes.


Dyslipidaemia is recognised as one of the most important risk factors for atherosclerotic cardiovascular disease (ASCVD). High levels of low‐density lipoprotein (LDL), and low levels of high‐density lipoprotein (HDL), are associated with myocardial infarction and stroke. In line with this information, LDL is considered the &ldquobad&rdquo cholesterol, and lower levels are better, while HDL is considered the &ldquogood&rdquo cholesterol, and higher levels are better. However, the protective role of HDL cholesterol (HDL-C) has been seriously challenged by the evidence from recent genetic, epidemiologic and clinical trials.

Lower LDL is better

There is now overwhelming evidence from different types of clinical and genetic studies that higher LDL cholesterol (LDL-C) is a potent cause of ASCVD [1].

A recent meta-analysis, evaluating the safety and effectiveness of lowering LDL-C, has revealed that there is a consistent relative risk reduction in major cardiovascular events per change in LDL in patient populations starting as low as a median of 63 mg/dL (1.6 mmol/L) [2]. In addition, findings from a pre-specified, secondary analysis of the FOURIER trial found a monotonic relationship between achieved LDL-C and major cardiovascular outcomes down to LDL-C concentrations of less than 7 mg/dL (0.2 mmol/L) [3]. It seems that there is no lower threshold for LDL below which no further decline in ASCVD occurs. Of importance, such low levels have not been associated with increased adverse events.

Evidence from genetic trials also suggests that disorders of low LDL-C are associated with protection from coronary disease [4]. Moreover, Mendelian randomisation studies have shown that prolonged exposure to lower LDL-C beginning early in life is associated with a significant reduction in the risk of coronary heart disease in a log-linear fashion, and that this reduction is substantially greater than the current practice of lowering LDL-C beginning later in life [4].

Is higher HDL better?

Many observational studies have demonstrated that low levels of HDL-C are associated with an increased risk of coronary heart disease [5-7]. The Framingham Study was the first and most important epidemiologic trial showing a strong, graded, independent, inverse relationship between HDL-C and both cardiovascular disease and total mortality [5]. HDL&rsquos cardiovascular protective effect has conventionally been attributed to its important role in the transportation of excess cholesterol from the peripheral tissues to the liver, the process also known as reverse cholesterol transport [8]. Besides, HDL seems to have anti-inflammatory [9], anti-oxidant [10], and antithrombotic properties [11] which may contribute to its atheroprotective effects.

On the other hand, recent data challenge whether HDL-C really protects against ASCVD. Mendelian randomisation studies have consistently shown that increased HDL-C levels caused by common variants in HDL-related genes are not necessarily associated with lower incidence of cardiovascular events [12,13]. Indeed, patients with certain mutations in CETP, ABCA1, LIPC, and SCARB1 were found to have paradoxically increased risk of coronary heart disease despite having very high concentrations of HDL-C [14,15]. This is in contrast to the Mendelian randomisation studies suggesting a strong association between LDL-C and increases in ASCVD [4].

Large-scale prospective cohort studies also contradict the previous finding of a linear inverse relationship between HDL and cardiovascular disease [7,16-18]. Although it is a common finding that low levels of HDL predict increased cardiovascular risk, data from several cohorts have revealed a plateau in the inverse association above certain HDL levels. There is even a suggestion of increased cardiovascular outcomes in those with extremely high HDLs.

A meta-analysis of 68 long-term prospective cohort studies including 302,430 people without initial vascular disease has revealed that there is no further decrease in coronary heart disease events with HDL values higher than

60 mg/dL (1.5 mmol/L) [7]. Likewise, in a pooled analysis from six community-based cohorts, Wilkins et al observed evidence of a plateau effect for coronary risk at HDL-C values >90 mg/dL in men and 75 mg/dL in women [16]. Recently, Madsen et al [17] examined the association of significantly elevated serum HDL-C concentrations with outcomes in two large population-based cohorts from Denmark (52,268 men and 64,240 women). For cardiovascular disease endpoints, they found a plateau around an HDL value of 58 mg/dL (1.5 mmol/L) and 77 mg/dL (2.0 mmol/L) for men and women, respectively, with no further decrease in risk with concentrations of HDL-C higher than that. Of note, the association between HDL-C concentrations and all-cause mortality was U-shaped, with both extremely high (>97 mg/dl for men, >116 mg/dl for women) and low concentrations being associated with increased risk [17] (Figure 1). A similar conclusion has been reached by Bowe et al [18], who evaluated the relationship between HDL-C and risk of death in a study involving 1.7 million United States veterans followed for over nine years. They found that HDL-C and risk of mortality exhibited a U-shaped association where risk of death is increased at low and high HDL-C levels.

Figure 1. HDL cholesterol and risk of all-cause mortality in the general population.

Adapted with the permission of Oxford University Press on behalf of the European Society of Cardiology from Madsen MC et al. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 201738:2478-86. [17].

The aforementioned data suggest that the old and the new observational studies yield different results regarding the cardiovascular effects of high HDL-C. At this point, it is important to highlight that the sample size of individuals with very high HDL-C (i.e., >80 mg/dL) was very small in most of the older studies, which limits the ability to draw conclusions about the risks for cardiovascular disease and total mortality associated with higher levels of HDL-C [16]. Furthermore, as mentioned by Madsen et al [17], in many of these studies individuals were categorised into larger groups, such as quintiles, and the focus was on low concentrations of HDL-C, thereby failing to elucidate associations at higher concentrations.

A similar pattern of results against the protective effects of higher HDL was obtained in randomised intervention trials carried out with niacin, fibrates, and cholesteryl ester transfer protein inhibitors. Despite being efficient at increasing HDL values, none of them was able to reduce all-cause mortality or cardiovascular events [19].

Considered together, current data establish that higher HDL-C is not necessarily protective against cardiovascular disease and may even be harmful in extremely high values. Indeed, current European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) dyslipidaemia guidelines emphasise that the risk of ASCVD appears to increase when HDL-C is above 90 mg/dL (2.3 mmol/L) [20]. On the other hand, it is not clear why very high levels of HDL-C could have negative effects while lower levels are predictive for increased cardiovascular risk. It is conceivable that plasma HDL-C concentration may not be a reliable indicator of the vascular protective function of HDL, which is very complex. Extreme elevations in HDL may represent dysfunctional HDL in some individuals, which may promote rather than protect against cardiovascular disease. Another possible explanation is that genetic mutations leading to very high HDL may also confer adverse vascular risk by unknown mechanisms.

Although the bulk of new data suggests that higher HDL-C levels are not associated with better outcomes, it should be noted that the neutral or negative effects of very high HDL have yet to be proven.

HDL cholesterol as a measure of 10-year cardiovascular risk

Current guidelines recommend the use of total cardiovascular risk assessment tools as an important step in decision making for primary prevention of cardiovascular disease. HDL-C is one of the risk measures used in commonly utilised risk tools such as the Framingham Risk Score ( and American College of Cardiology/American Heart Association (ACC/AHA) pooled cohort ASCVD risk calculator ( The European Society of Cardiology also recommends measuring HDL-C to refine risk estimation further. We routinely use HeartScore, the electronic and interactive version of the European SCORE risk charts (

In order to evaluate the impact of different HDL levels on cardiovascular risk estimation better, let us calculate the 10-year risk of a 53-year-old healthy man who denies having coronary artery disease risk factors, such as diabetes, cigarette smoking, hypertension, hypercholesterolaemia or family history of heart disease. Let us assume his blood pressure is 130/75 mmHg and his lipid profile is as follows:

- total cholesterol 212 mg/dL

The estimated cardiovascular risk of this patient, with regard to different HDL-C levels, is given in Table 1. It is noteworthy that the risk of cardiovascular death decreases constantly in parallel with the increase in HDL values, without any threshold level. For example, the estimated cardiovascular mortality risk at an HDL-C level of 117 mg/dL (>116 mg/dL) corresponds to half the predicted risk at an HDL-C level of 88 mg/dL (1% vs 2%). Likewise, the risk at 88 mg/dL corresponds to half the predicted risk at 58 mg/dL (2% vs 4%). The results are more or less the same when the ACC/AHA or Framingham risk tools are applied instead of HeartScore. Apparently, existing risk assessment tools have not yet been adapted to take into account the current evidence that very high HDL-C fails to protect against ASCVD. Indeed, recent European guidelines recommend not using HDL as a risk measure when HDL-C values are above 90 mg/L (2.3 mmol/lL) [20].

Table 1. Estimated 10-year cardiovascular mortality risk of a patient by different HDL-C levels according to the HeartScore tool (

Gender Age, years SBP, mmHg Smoking Total cholesterol, mg/dL HDL cholesterol, mg/dL Estimated 10-year cardiovascular mortality risk
Male 53 130 No 212 27 7%
42 5%
58 4%
73 3%
88 2%
>116 1%


There is a discrepancy between recent data and the currently accepted knowledge regarding the role of higher HDL cholesterol values on cardiovascular outcomes. However, the positive, neutral or negative influence of very high HDL has not yet been fully elucidated and remains a matter of debate. Until this topic has been clarified, we should keep in mind that HDL cholesterol may not be as protective as we believe. The current risk estimation tools may underestimate the cardiovascular risk of individuals with very high HDL values which may potentially lead to underuse of cardioprotective medicines such as statins.


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Notes to editor

Sadi Güleç, MD Çetin Erol, MD, FESC

Department of Cardiology, Ankara University, School of Medicine, Ankara, Turkey

Address for correspondence:

Ankara Univesrsitesi, Tıp Fakültesi,Ibni Sina Hastanesi,Kardiyoloji Anabilim Dalı,Samanpazarı, Ankara,Turkey



Apolipoprotein B containing lipoproteins are atherogenic. There is evidence that with low plasma low density lipoprotein cholesterol (LDL-C) levels residual vascular risk might be caused by triglyceride rich lipoproteins such as very-low density lipoproteins (VLDL), chylomicrons and their remnants. We investigated the relationship between VLDL-cholesterol (VLDL-C) and recurrent major adverse cardiovascular events (MACE), major adverse limb events (MALE) and all-cause mortality in a cohort of patients with cardiovascular disease.


Prospective cohort study in 8057 patients with cardiovascular disease from the UCC-SMART study. The relation between calculated VLDL-C levels and the occurrence of MACE, MALE and all-cause mortality was analyzed with Cox regression models.


Patients mean age was 60 ± 10 years, 74% were male, 4894 (61%) had coronary artery disease, 2445 (30%) stroke, 1425 (18%) peripheral arterial disease and 684 (8%) patients had an abdominal aorta aneurysm at baseline. A total of 1535 MACE, 571 MALE and 1792 deaths were observed during a median follow up of 8.2 years (interquartile range 4.512.2). VLDL-C was not associated with risk of MACE or all-cause mortality. In the highest quartile of VLDL-C the risk was higher for major adverse limb events (MALE) (HR 1.49 95%CI 1.16–1.93) compared to the lowest quartile, after adjustment for confounders including LDL-C and lipid lowering medication.


In patients with clinically manifest cardiovascular disease plasma VLDL-C confers an increased risk for MALE, but not for MACE and all-cause mortality, independent of established risk factors including LDL-C and lipid-lowering medication.


Sociodemographic and laboratory characteristics of the participants

The study included 2479 pregnant women, the mean age of the study population was 29.3 ± 4.2 years, the percentage of more frequency of maternal education (≥9 years) was 60.7% (n = 1505). The mean pre-pregnancy BMI was 21.2 ± 2.8 kg/m 2 , and 42.3% (n = 1049) of participants were multipara. The mean of serum 25(OH)D and hs-CRP concentrations were 40.08 nmol/L (SD:16.69, range:10.00–114.00) and 3.03 mg/L (SD:2.07, range:0.20–10.00), the percentage of the participants who had vitamin D deficiency was 75.6% (n = 1875). The mean of serum TC, TG, HDL-C, and LDL-C concentrations were 5.99 mmol/L (SD:1.01, range:2.90–9.71), 2.61 mmol/L (SD:1.02, range:0.80–9.87), 2.02 mmol/L (SD:0.35, range:0.76–3.67), and 2.85 mmol/L (SD:0.70, range:0.70–7.42), respectively (Table 1).

Association of lipid profile and hs-CRP levels in the second trimester

Polynomial fitting revealed a significant non-linear correlation between lipids level (TC: R 2 = 0.520, P = 0.036 TG: R 2 = 0.931, P <0.001 HDL-C: R 2 = 0.457, P = 0.001 LDL-C: R 2 = 0.750, P = 0.006) and hs-CRP, respectively (Fig. 1). The U-shaped nature of the association of TC and LDL-C with hs-CRP was confirmed with cubic-fitting model. After adjustment for confounding, compared with the medium level of lipid profile group, the hs-CRP levels in the low (adjusted β: 0.040, 95%CI: 0.009,0.071) or high (adjusted β: 0.043, 95%CI: 0.012,0.074) level group of TC, high leaves of TG (adjusted β: 0.040, 95%CI: 0.010,0.070), or low LDL-C (adjustedβ: 0.050, 95%CI: 0.020,0.080) levels were significantly elevated, while hs-CRP was significantly reduced only at low TG (adjustedβ: -0.077, 95%CI:-0.108,-0.047) levels. However, there was no significant association between HDL-C and hs- CRP (Table 2).

Non-linear relationship between lipid profile and hs-CRP in the second trimester

Association of 25(OH)D status with lipid profile and hs-CRP in the second trimester

Table 3 shows the relationship between 25(OH)D status with lipid profile and hs-CRP in the second trimester of pregnancy. Adjusted multiple linear regression analyses revealed a significant negative correlation between serum 25(OH)D with TC, TG, HDL-C, LDL-C, and hs-CRP. Compared with vitamin D deficiency group, the levels of TC, TG, HDL-C, LDL-C and hs-CRP in the non-vitamin D deficiency group significant decrease by 8.690 mg/dL (95%CI: 5.046,12.333), 13.254 mg/dL (95%CI: 4.963,21.544), 1.910 mg/dL (95%CI: 0.644,3.176), 4.933 mg/dL (95%CI: 2.409,7.458), and 0.034 mg/L (95%CI: 0.004,0.064), respectively.

Relationship between lipid profile and hs-CRP in different levels of vitamin D

Stratification by 25(OH)D level was performed to further explore the association of lipid profile and hs-CRP (Table 4). Compared with medium levels of lipids group, hs-CRP levels are higher in pregnant women with high TC or TG levels, and pregnant women with lower levels of TC, HDL-C or LDL-C also have higher hs-CRP levels in the vitamin D deficient group. However, in the non-vitamin D deficient group, a higher lipid profile was not associated with increased hs-CRP levels. Additionally, there was a significant association of lower levels of TG with decreased hs-CRP.

HDL-C was not included in path analysis because no significant association between 25(OH)D and HDL-C was found. For the comparative fit index, normal fit index, and the root mean square error of approximation of our path model, values were 0.781, 0.870, 0.001, respectively, reflecting an acceptable fit. Supplemental Figure 2 shows that a 1 nmol/L increase in 25(OH)D was associated with a 20%, a 10%, and a 23% decrease in TC, TG and LDL-C concentrations (P < 0.05). If the TG concentration increased by 1%, we would expect hs-CRP to increase by 0.02 mg/L (P < 0.05). Mediators that had appreciable shares of the associations between 25(OH)D and hs-CRP was TG (10.2% of the association β = − 0.011 total indirect effect: 95% CI: − 0.019, − 0.002).

The role of 25(OH)D in the relationship between lipid profile and hs-CRP in the second trimester

We further assessed the role of 25(OH)D status in the relationship between lipid profile and hs-CRP in the second trimester by cubic model, the solid black line shows the best fit analysis (TC: R 2 = 0.68, P = 0.03 TG: R 2 = 0.14, P = 0.81 HDL- C: R 2 = 0.63, P = 0.03 LDL-C: R 2 = 0.41, P = 0.21) (Fig. 2). After adjusting for confounds, this model suggested a steep increase in the adjusted regression coefficient of lipid with hs-CRP up to 50 nmol/L of 25(OH)D, and the highest adjusted regression coefficients were observed in pregnant women with 25(OH)D above 50 nmol/L.

The role of vitamin D in the relationship between lipid profile and inflammation in the second trimester. a.25(OH)D, 25-hydroxyvitamin D hs-CRP, high-sensitivity C-reactive protein TC, total cholesterol TG, triglyceride HDL-C, high density lipoprotein-cholesterol LDL-C, low density lipoprotein-cholesterol Note: The ordinates denote the adjusted regression coefficient of the multiple linear regression of lipid profile and hs-CRP, and the abscissa denote the 25(OH)D level in the second trimester the solid black line denote the correlation between vitamin D levels with lipid profile and hs-CRP in the second trimester, and the shaded area indicates a 95% confidence interval. The closer the distance of the solid line from the X axis, the stronger the correlation strength between the two. Adjusted for sociodemographic characteristics (maternal age, education, income, season, parental diabetes and parental rheumatism), perinatal health status(pre-pregnancy BMI, systolic blood pressure and diastolic blood pressure), lifestyle(sitting or lying time, physical activities, paternal alcohol and smoking consumption, fish oil supplement, multivitamin supplement, milk intake, soy product intake and dessert intake)

Author information


Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, 100730, China

Meicen Zhou, Fan Ping, Wei Li & Yuxiu Li

Nankou Community Health Service Centers, Changping District, Beijing, 102200, China

Nankou Railway Hospital, Changping District, Beijing, 102200, China

Department of Nutrition, Peking Union Medical College Hospital, Beijing, 100730, China