Non–High-Density Lipoprotein Cholesterol as the therapeutic target

What a relevant question. 

Is non-HDL cholesterol adequate, or do we need to measure apolipoprotein B to assess cardiovascular risk.  This paper addresses that question.  I liked the subheading “do the Math” 

It starts by reminding us that current guidelines rely on LDL-C  as the primary therapeutic target in the prevention of cardiovascular disease.  They go on to point out the limitations of LDL.  Only 30% reduction in ACS and less predictive value in the metabolic syndrome which is becoming increasingly prevalent.  The metabolic syndrome may increase VLDL and other lipoproteins which are atherogenic, but not accounted for by LDL-C alone.  The Apolipoprotein B seems like a likely candidate, since it seems to be associated with most atherogenic particles, therefore giving an aggregate number of all atherogenic particles. 

A simple way of doing this may be non-HDL cholesterol which is the Total Cholesterol (TC) minus the HDL (HDL-C) [TC-HDL-C].  An interesting question is the comparison of apo-B to non-HDL cholesterol.  This paper rightfully points out the significant high correlation of the two variables, and the inability of apo-B to independently outperform non-HDL cholesterol.

The concluding remarks compare and contrast apo-B with non-HDL cholesterol and leads to my same conclusion: 

“Non-HDL cholesterol is a more realistic primary target of therapy, given its ease of use and implementation” 


1.  Non–High-Density Lipoprotein Cholesterol Versus Apolipoprotein B in Cardiovascular Risk Stratification  doi:10.1016/j.jacc.2011.05.009 J Am Coll Cardiol 2011;58:457–63

Bryan E Fuhs MD                                                                                         reviewed 9/2/2011

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Ezetimibe ( Zetia ) and Phytosterols

I had wondered if using phytosterols and ezetimibe together would have any effect on lipid lowering.  I am glad to see that the combination was studied recently and reported. (1) 

My take home on this article is that the combination of ezetimibe and phytosterols lowered LDL and non-HDL cholesterol more than ezetimibe alone.  The reported benefit was a drop from LDL of 129 mg/dL to 108 mg/dL with ezetimibe and  to 101 mg/dL when combined with with phytosterols.  It does sound more impressive when you say ezetimibe drops the LDL by 16% and ezetimibe and phytosterols drops it by 22% relative to placebo.  Non-HDL cholesterol dropped about the same amount when reported with 158 mg/dL to 135 mg/dL to 128 mg/dL which is probably the same absolute drop, but percentages of course are different being 14% and 18%.  Also of interest was that triglycerides dropped with each treatment, but more with the ezetimibe and phytosterols than other treatments.  It was noted in the article that ezetimibe did raise the HDL statistically compared with placebo or ezetimibe and phytosterols, however the numbers were 38 mg/dL vs 40 mg/dL vs 39 mg/dL, which does not seem all that biologically important.

What foods are high in phytosterols (2) .  In mg/100mg Oils have the highest concentration: Rice Bran 1055, Corn 952, Wheat germ 553, Flax seed 338, Cottonseed 327, Soybean 221, Peanut 206, Olive 176, Coconut 91 and Palm 49.    Most fruits and Vegetables are not great sources of plant sterols, but Nuts and Legumes do have more than most. (160 to 120). 

This suggests that a diet rich in plant sterols (phytosterols) will enhance the effect of ezetimibe.  I am not advocating additives, but I again suggest a diet rich in whole grains, nuts, fruits and vegetables.  This study shows one of the ways that diet may be helpful.   

1.  Combined Effects of Ezetimibe and Phytosterols on Cholesterol metabolism: A Randomized, Controlled Feeding Study in Humans  doi:10.1161/CIRCULATIONAHA.110.006692


Bryan E Fuhs MD                                                                                           reviewed 8/29/2011      

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Excellent Nutrition Information

Good Food Book by Gabe and Diana Mirkin is available on the web.  It is easy to understand and a great starting point for a lifetime plan of healthy eating.  I encourage patients to read it and follow their suggestions.

They have graciously posted it on their informative web site.

Bryan E Fuhs MD                                                                                  Reviewed    05/19/2011

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Using Hemoglobin A1C ( HgbA1C ) for diagnosing Diabetes

The use of HgbA1C for diagnosis of diabetes changed in 2010, when the American Diabetes Association (ADA) revised criteria for the diagnosis of diabetes mellitus. In addition to the fasting glucose (FPG), oral glucose tolerance test (OGTT), the Hemoglobin A1c > 6.5 (HgbA1C) was accepted as another way to diagnose diabetes

This cutpoint ( 6.5% ) is acknowledged to classify fewer individuals as diabetic than using the standard FPG >125 mg/dL. The FPG >125 better correlates with plasma glucose of 200 or greater. Several studies have suggested increase of diabetic retinopathy when plasma glucose is greater than 200, so a marker that correlates would be helpful.

Hemoglobin A1C is accepted as the best measure of average glucose. HgbA1C has been shown to correlate with likelihood of diabetic retinopathy in a linear fashion, and as expected specificity increases as the cut-point is raised.  A HgbA1C of 6.5% is estimated to have a specificity of 99% for identifying diabetics.

The cut-point of 6.5  was chosen because moderate to severe retinopathy was rarely found below that level, but there were no mathematical models able to identify a clear, objective cut-point. This is a concern, because above 6.0% there is increasing retinopathy in some studies.  In a Japanese study the optimal cut-point or inflection point would have been 5.3-5.5% for the development of retinopathy. There is growing data that retinopathy, microalbuminuria, chronic kidney disease and peripheral neuropathy may have a continuous linear relationship to the HgbA1C which makes choosing a cut-point difficult.

Comparison of the 3 ways of diagnosing diabetes shows that HgbA1c is the least sensitive and may miss 70% of the diabetics. The 2 hour post prandial plasma glucose (OGTT) better identifies diabetics by almost a 3:1 margin compared with HgbA1c and 2:1 margin compared with fasting glucose >125. This suggests that HgbA1C, FPG, and OGTT measure different facets of glycemia.

Lowering the cut point on the HgbA1C might be suggested, but the positive predictive value has been shown to drop from 93% to 24% if the HgbA1C is moved from 6.5% to 5.8%. Suspicion of diabetes may require more workup then just a HgbA1C.


  • A HgbA1C of greater than 6.5% is a specific diagnosis for diabetes, but many diabetics will not be identified using this definition. 
  • It does appear that HgbA1C in this range is a risk factor for development of coronary artery disease (CAD).

It would be nice to have studies of people with a HgbA1C between 5.5 and 6.5 to make a more rational treatment decision.  Evidence suggests that there are some people in this range (5.5-6.5) that are diabetics, and will have neuropathy, retinopathy, chronic kidney disease including macro and microalbuminuria. 

  • Therefore, while a HgbA1C of 6.5 will diagnosis a diabetic, a HgbA1c of 5.5-6.5 does not exclude diabetes. 

    Bryan E Fuhs MD                                              Reviewed 5/18/2011
  1. Implications of Using Hemoglobin A1C for Diagnosing Diabetes Mellitus; Samir Malkani, MD, John Pl Mordes MD The American Journal of Medicine (2011) 124, 395-401
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500 calories a day

Funny what simple concepts resonate with people. This brief snippet was worked into a story and continues to get numerous hits over at KHQ. This is the link to the comment:

500 calories a day

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Rate vs Rhythm Control

Atrial fibrillation can be managed either by controlling the rate or trying to re-establish sinus rhythm. The pendulum is currently favoring the rate control strategy (with adequate anticoagulation)

I think the AFFIRM trial did the most to change medical opinion that rate control is an adequate strategy. Until then, we settled for rate control, but only after numerous attempts at regaining sinus rhythm. This trial suggested that rate control was not such a bad strategy.

My initial thoughts about the AFFIRM trial were that three months of anticoagulation after cardioversion is not adequate and I still think that can be inferred from the data. However, it is much more often quoted as a reason to move to rate control strategy and quit trying to re-establish sinus rhythm.

The original study on average enrolled 70 year old patients, 39% female, 26% with CAD and 23% with CHF. They followed for 3.5 years. The rate control group had significantly fewer hospitalizations and the trend was towards less all cause mortality and less CNS events.

This study certainly has become the cornerstone of the argument for rate control, although several other well done studies do point towards the same conclusions. However, patients enrolled into the study were essentially asymptomatic in Afib to get into the study. Many of the groups advocating rate control, omit that big limitation. The age also may be important, since strategies for 70 year olds may not fit a 30 year old, and the followup period was only 3.5 years.

I still think that the key to therapy is deciding whether a patient is truly asymptomatic. Often I will cardiovert the patient just to ascertain that they truly are asymptomatic. The truly asymptomatic, can be safely and effectively managed with a rate control strategy. But I think that the symptomatic patient is not who the AFFIRM trial addressed and should not be assigned to a rate control strategy initially.

  1. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators, “A comparison of rate control and rhythm control in patients with atrial fibrillation”, N Engl J Med (2002);347: pp. 1825–1833.
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CHADS2 and Risk

It is amazing the power of numbers to predict, and our inability to accurately judge risk. The CHADS Score predicts the risk of stroke on a yearly basis, depending on the number of risk factors you have. Most people understand that risk calcultion, but more worrisome is the likelihood of the event occuring given time. I have calculated 1 year risk, but then also placed the 5, 10, 15 and 20 year risk for stroke using the same estimated frequency. I think that many people would make different choices about anticoagulation if they recognized the cumulative risk.

CHADS2 Score Stroke Risk % Year 1 Year 5 Year 10 Year 15 Year 20
0.0 1.9 1.9 9.1 17.5 25.0 31.9
1.0 2.8 2.8 13.2 24.7 34.7 43.3
2.0 4.0 4.0 18.5 33.5 45.8 55.8
3.0 5.9 5.9 26.2 45.6 59.8 70.4
4.0 8.5 8.5 35.9 58.9 73.6 83.1
5.0 12.5 12.5 48.7 73.7 86.5 93.1
6.0 18.2 18.2 63.4 86.6 95.1 98.2

Another way of presenting that same data is, if you have two of the CHADS risk factors for stroke, you have a 18.5% risk for stroke in the next 5 years and a 33.5% risk in the next 10 years. I think that would help guide the decision to take Coumadin, which is the standard recommendation if you have a CHADS score of 2.

Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ (2001). “Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation”. JAMA 285 (22): 2864–70. doi:10.1001/jama.285.22.2864. PMID 11401607
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CHADS Calculation

The current risk stratification for stroke most widely used is CHADS2. This system uses common clinical conditions to assess risk for stroke. Points are assigned, and anticoagulation is given depending on how many points the patient has:

C Congestive heart failure 1
H Hypertension: blood pressure consistently above 140/90 mmHg (or treated hypertension on medication) 1
A Age ?75 years 1
D Diabetes Mellitus 1
S2 Prior Stroke or TIA 2

This system is simple, easy to apply and used clinically. The current (5/2011) recommendations are:

0 Low risk Aspirin

1 Moderate Risk Anticoagulation (Coumadin, Pradaxa) or ASA

2 or < High Risk Anticoagulation (Coumadin, Pradaxa)

All of these strategies need adjustment for risk of serious bleeding.

There is a newer system available, the CHA2DS2-VASc score [Congestive heart failure, Hypertension, Age ?75 years (doubled), Diabetes mellitus, Stroke (doubled), Vascular disease, Age 65–74 years, Sex category] which does make it more risky to have peripheral vascular disease, be female, or be older than 75, which may refine risk.

However, the main point is that clinical factors predict risk, and those factors are what are used to determine who should get aggresive anticoagulation.

Gage BF, van Walraven C, Pearce L, et al. (2004). “Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin”. Circulation 110 (16): 2287–92. doi:10.1161/01.CIR.0000145172.55640.93. PMID 15477396.
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ (2001). “Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation”. JAMA 285 (22): 2864–70. doi:10.1001/jama.285.22.2864. PMID 11401607
Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ: Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The euro heart survey on atrial fibrillation. Chest 2010;137:263272.
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Atrial Fibrillation

This rhythm seems to provide countless nuanced discussions. The rhythm itself often brings a patient to medical attention, but the real concern is the stroke risk.

At this point, our way of risk assessing the likelihood of stoke is the CHADS or CHADS2 score. Ultimately, this is just a tool that says being old, having or being treated for hypertension, having diabetes, having congestive heart failure or previously having a stroke or TIA make it more likely to have a stroke. Saying it that way makes it sound so common sense. It also is interesting in what it doesn’t say.

There is nothing that says the amount atrial fibrillation is predictive of who will have a stroke. That is not so intuitive. It would seem that the greater the burden of atrial fibrillation that the stroke risk should be higher, but it is at best a weak predictor

This leads to a dilemma, the patient is complaining of a rhythm problem, and the important part of the treatment never addresses the symptom the patient is having. It is not all that surprising that neither of us feel like we have communicated our concerns at the end of an appointment that is now often less than 8 minutes.

Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ (2001). “Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation”. JAMA 285 (22): 2864–70. doi:10.1001/jama.285.22.2864
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It is getting increasingly hard for me to realize that Diabetes Type II is often treatable by diet, and that most people choose not to change thier diet to prevent diabetes. Avoiding refined carbohydrates and being careful with root vegetables and rice can make a significant difference in the outcome of diabetes.

The idea of Glycemic Index, (or Glycemic Load) really seems to be at the heart of this treatment. But practically it means avoiding products made from flour (Bread, Pasta and processed foods). By adding this advice to increasing the plants in the diet (like the DASH diet) significant benefit could be seen in Diabetes, Heart Disease, Stroke and likely Arthritis. Hard to believe that simple advice is so hard to follow considering the consequences.

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