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Thursday, December 20, 2012

Current State of Niacin in Cardiovascular Disease Prevention - JACC

The Current State of Niacin in Cardiovascular Disease Prevention: Title and subTitle BreakA Systematic Review and Meta-Regression

Paul M. Lavigne, MD; Richard H. Karas, MD, PhD

Abstract

Objectives This study sought to assess the efficacy of niacin for reducing cardiovascular disease (CVD) events, as indicated by the aggregate body of clinical trial evidence including data from the recently published AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial.
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Conclusions The consensus perspective derived from available clinical data supports that niacin reduces CVD events and, further, that this may occur through a mechanism not reflected by changes in high-density lipoprotein cholesterol concentration.
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Conclusions

Although potentially indicative of limited efficacy in select patients, the recently published findings of AIM-HIGH are insufficient to alter the aggregate available data supporting the clinical efficacy of niacin therapy as a means to reduce CVD risk. The present analysis demonstrates the summary effect of niacin across a broad clinical population to confer atheroprotection and cautions against the extension of recent isolated findings to substantially alter overall clinical practice. These results thus underscore the need for further analysis, including that offered by the ongoing HPS2-THRIVE (Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events) trial, to more clearly define the role of niacin in current practice.

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Digby J.E., McNeill E., Dyar O.J., Lam V., Greaves D.R., Choudhury R.P.. Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin, Atherosclerosis 2010 209 () 89-95
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Linke A., Sonnabend M., Fasshauer M.. et al. Effects of extended-release niacin on lipid profile and adipocyte biology in patients with impaired glucose tolerance, Atherosclerosis 2009 205 () 207-213
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Lee J.M.S., Robson M.D., Yu L.-M.. et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study, J Am Coll Cardiol 2009 54 () 1787-1794
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Wu B.J., Yan L., Charlton F., Witting P., Barter P.J., Rye K.-A.. Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids, Arterioscler Thromb Vasc Biol 2010 30 () 968-975
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Roche Inc, Roche Provides Update on Phase III Study of Dalcetrapib [press release]. May 2012, () -
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Stein E.A., Stroes E.S.G., Steiner G.. et al. Safety and tolerability of dalcetrapib, Am J Cardiol 2009 104 () 82-91
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Alsheikh-Ali A.A., Karas R.H.. Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone (from the United States Food and Drug Administration adverse event reporting system), Am J Cardiol 2007 99 () 379-381
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Reas the complete article here.

Wednesday, December 19, 2012

Friday, December 14, 2012

Drug company kills off another cholesterol-modifying drug - Briffa

Drug company kills of another cholesterol-modifying drug
I rarely meet someone who has not heard of cholesterol and does not believe it to be a largely dangerous substance. And increasing number of people seem to be aware of the conventional wisdom regarding the different forms of cholesterol, specifically low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C). Actually, these names are a bit misleading, as these particles are not cholesterol (though they do contain cholesterol). But, anyway, the conventional wisdom is that LDL-C dumps cholesterol on the inside of our arteries while HDL-C clears cholesterol. As a result, LDL-C and HDL-C are often dubbed ‘bad-’ and ‘good-’ cholesterol.

The most commonly prescribed cholesterol drugs are known as statins, and their main mechanism of action is to lower LDL-C levels. However, other types of cholesterol-modifying drugs exist, including a relatively new class known as cholesterylester transfer protein inhibitors (CEPT inhibitors), which the conversion of supposedly healthy HDL-C into supposedly unhealthy LDL-C. If you believe the conventional wisdom on cholesterol (I don’t), then this should translate into benefits for health with regard cardiovascular disease (e.g. heart disease and stroke).

All this theory is meaningless, however. The only important thing is not the effect drugs (or anything else) have on cholesterol levels, it’s the impact they have on health. Some years back the drug company Pfizer spent in the region of $800 million developing a CEPT inhibitor by the name of torcetrapib. It had ‘positive’ effects on LDL-C and HDL-C levels, but also turned out to kill people. Pfizer promptly and quite rightly ceased development of the drug.

The crashing failure of torcetrapib has not stopped other drug companies seeking to find a commercially viable CEPT inhibitor of their own. More recently, drug company Roche invested in the development of a drug known as dalcetrapib. However, in the middle of this year Roche abandoned plans for further development, and a recently-published study shows us why [1].

In this study, published in the New England Journal of Medicine, almost 16,000 patients who had suffered from ‘acute coronary syndrome’ (e.g. angina or heart attack) were treated with dalcetrapib or placebo for an average of about two and a half years.

These are just the sort of patients one would expect to benefit most from an intervention because, as a group, they would generally be at high risk of future problems. Also, the number of subjects here is huge, and therefore more than big enough to detect any real benefit the drug may have.

The researchers assessed the effects of dalcetrapib using a ‘composite endpoint’ – which essentially means lumping several outcomes together. The composite outcome included death from heart disease, non-fatal heart attack, ischemic stroke (strokes due to blockage of blood vessels rather than bleeding), unstable angina (angina that can come on at rest), and cardiac arrest with resuscitation. The use of composite endpoints ups the odds that a ‘statistically significant’ benefit for a drug will be found (compared to when only one single outcome is chosen).

Biochemical analysis revealed that dalcetrapib did, as expected, have considerable HDL-boosting effect. But the study showed that this drug had no benefits for health at all.

Another interesting thing about the study was that dalcetrapib was found to increase markers of inflammation – a process which is believed to play a key part on the development of heart disease and stroke.

This study was originally designed to run for longer but was terminated early once these results were in. Early termination of studies is known to generally inflate the benefits of drugs and downplay their risks. Who knows what may have happened if they’d continued.

Of course you’re unlikely to hear about the dalcetrapib study because it wasn’t announced with the blaze of publicity usually afforded to more ‘positive’ studies about cholesterol-reducing drugs. But this is often the way with cholesterol-related research in particular: positive results are spun in a way which gives medication seeming miraculous properties, while negative results and inconvenient truths are swept under the carpet.

References:
1. Schwartz GG, et al. Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 29 November 2012 (epub)
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Read the complete article here.

Monday, December 10, 2012

Scant Evidence That Salt Raises BP - Kaiser

Scant Evidence That Salt Raises BP, Review Finds

The evidence for health benefits associated with salt reduction is controversial and the "concealment of scientific uncertainty" is a mistake, researchers suggested.

Controversy about what effect too much sodium intake has on the body goes back to the early part of the 20th century, according to Ronald Bayer, PhD, and colleagues from Columbia University Mailman School of Public Health in New York City.

But in the last few years, the discourse has reached a fever pitch, they wrote online in Health Affairs.

In 2011, for example, the Journal of the American Medical Association published a study by Stolarz-Skrzypek et al. that found only a weak correlation between salt and blood pressure. An editorial in the Lancet lambasted the JAMA study as "disappointingly weak" and "likely to confuse public perceptions of the importance of salt as a risk factor for high blood pressure, heart disease, and stroke."

Also in 2011, the Cochrane Review published two studies finding little or no relationship with all-cause mortality and salt reduction. The Lancet criticized both the Cochrane Library and the authors, saying, "They have seriously misled the press and thereby the public."

One of those reviews had concluded that "after more than 150 randomized controlled trials and 13 population studies without an obvious signal in favor of sodium reduction, another position could be to accept that such a signal may not exist."

Bayer and colleagues cited several studies that could not find a link between salt intake and elevated blood pressure, including a 1967 study of the Framingham cohort, and Japanese and Scottish reports in the 1980s totalling 15,000 people that concluded the association between sodium and blood pressure is "extremely weak."

The researchers noted that most of the evidence pointed to the weakest of correlations between salt and blood pressure. Yet, the cause to reduce salt was taken up by government agencies with special speed.

They cited a 2010 Institute of Medicine report called "Strategies to Reduce Sodium Intake in the United States." In the report, the IOM claimed that the "harmful relationship of salt with hypertension has been known for 40 years," which Bayer and colleagues argue is debatable -- based on the evidence.

"The [IOM] report was welcomed by the incoming president of the the American Society of Hypertension," the investigators wrote, "who warned that the 'outcomes mafia' might challenge the justification for a regulatory approach."

In 2011, the FDA also called for data and recommendations "that would help it shape regulatory policy on salt in food."

"All the while, skeptics still were asking for the evidence," Bayer and colleagues wrote.
More than 20 years prior to the IOM report, C. Everett Koop, MD, the U.S. Surgeon General, issued a report noting that government agencies were "very quick to embrace the importance of salt reduction in the 1970s and 1980s, which stood in stark contrast for the snail's pace of recommendations related to reducing blood cholesterol levels."

The authors cited many more studies finding little association between salt and blood pressure that did not eliminate the stigma attached to the mineral.

Advocates for salt reduction questioned the science behind studies that didn't conform to their opinion, and proponents partially blamed the food industry because it was in their best interest to muddy the waters and keep the debate going.

One of the interesting things about this debate, Bayer and colleagues pointed out, was that you could find respected academics on both sides.

"At the most fundamental level, we believe that it is essential to recognize the role that judgment and values must play in evidence-informed policy making," the authors concluded.

"Science must remain open, skeptical, and concerned about unmeasured confounding and selection bias in studies that accompany even the best efforts to articulate the evidence for new interventions," they added.

The investigators said that one of the reviewers of this paper had asked, "In the end, does the harm of exaggerating certainty do more harm than good? After all, it would be very hard to make any policy from a position of informed, complicated, contextualized ambivalence."

They concluded that the "concealment of scientific uncertainty is a mistake that serves neither the ends of science nor good policy. Simplistic pictures of translation from evidence to action distort our ability to understand how policy is, in fact, made and how it should be made."
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Read the complete article here.

Another article here.

More data in the Salt Wars - Aug 14, 2014; http://www.medpagetoday.com/Cardiology/Hypertension/47203

An article by Marion Nestle - http://www.foodpolitics.com/2014/08/its-salt-arguments-again-new-research-arguments-over-public-health-recommendations-and-issues-of-conflicts-of-interest/

Thursday, December 6, 2012

The straight dope on cholesterol – Part IX - Attia

 Peter once again provides an excellent summary and then proceeds into Part 9 of his cholesterol tome.
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The straight dope on cholesterol – Part IX

The straight dope on cholesterol – Part IX
Previously, across 8 parts of this series we’ve laid the groundwork to ask perhaps the most important question of all:
What should you eat to have the greatest chance of delaying the arrival of cardiovascular disease?
Before we get there, since this series has been longer and more detailed than any of us may have wanted, it is probably worth reviewing the summary points from the previous posts in this series (or you can just skip this and jump to the meat of this post).

What we’ve learned so far

  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.
  31. HDL-C and HDL-P are not measuring the same thing, just as LDL-C and LDL-P are not.
  32. Secondary to the total HDL-P, all things equal it seems smaller HDL particles are more protective than large ones.
  33. As HDL-C levels rise, most often it is driven by a disproportionate rise in HDL size, not HDL-P.
  34. 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.
  35. 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.

Did you say “delay?”

That’s right. The question posed above did not ask how one could “prevent” or eliminate the risk cardiovascular disease, it asked how one could “delay” it. There is a difference. To appreciate this distinction, it’s worth reading this recent publication by Allan Sniderman and colleagues. Allan sent me a copy of this paper ahead of publication a few months ago in response to a question I had posed to him over lunch one day. I asked,
“Allan, who has a greater 5-year risk for cardiovascular disease, a 25 year-old with a LDL-P/apoB in the 99th percentile or a 75-year-old with a LDL-P/apoB in the 5th percentile?”
The paper Allan wrote is noteworthy for at least 2 reasons:
  1. It’s an excellent reminder that age is a paramount risk factor for cardiovascular disease.
  2. It provides a much better (causal) model for atherosclerosis than the typical age-driven models, and explains why age is an important risk factor.
What do I mean by this? Most risk calculators (e.g., Framingham) take their inputs (e.g., age, gender, LDL-C, HDL-C, smoking, diabetes, blood pressure) and calculate a 10-year risk score. If you’ve ever played with these models you’ll quickly see that age drives risk more than any other input. But why? Is there something inherently “risky” about being older?

Sniderman and many others would argue (and I agree) that the reason age is a strong predictor of risk has to do with exposure to apoB particles — LDL, Lp(a), and apoB-carrying remnants. Maybe it’s because I’m a math geek, but such models just seem intuitive to me because I think of most things in life in terms of calculus, especially integrals, the “area under a curve.”

[I once tried to explain to a girlfriend who thought I wasn’t spending enough time with her that my interest in her should be thought of in terms of the area under the curve, rather than any single point in time. That is, think in terms of the integral function, not the point-in-time function. Needless to say, she broke up with me on the spot (in the middle of a parking lot!), despite me drawing a very cool picture illustrating the difference, which I’ve re-created, below.]
Integral
The reason age is such a big driver of risk is that the longer your artery walls are exposed to the insult of apoB particles, the more likely they are to be damaged, for all the reasons we covered in Part IV of this series. [This paper also reviews the clinical situation of PCSK9 mutations which builds a very compelling case for the causal model of apoB particles in the development of atherosclerosis].

What does eating have to do with cardiovascular risk?

So now that everyone is on the edge of their seat in anticipation of this punch-line, let me provide two important caveats.
First, there are no long-term studies – either in primary or secondary prevention – examining the exact question we all want to know the answer to with respect to the role of dietary intervention on cardiovascular disease. There are short-term studies, some of which I will highlight, which look at proxies for cardiovascular disease, but all of the long-term studies (looking at secondary prevention), are either drug studies or multiple intervention studies (e.g., cholesterol-lowering drug(s) + blood pressure reducing drug(s) + dietary intervention + exercise + …).
In other words, the “dream” study has not been done and won’t be done for a long time. The “dream” study would follow 2 randomized groups for many years and only make one change between the groups. Group 1 would consume a standard American diet and group 2 would consume a very-low carbohydrate diet. Furthermore, compliance within each group would be excellent (many ways to ensure this, but none of them are inexpensive – part of why this has not been done) and the study would be powered to detect “hard outcomes” (e.g., death), instead of just “soft outcomes” (e.g., changes in apoB, LDL-C, LDL-P, TG).
Second, everything we have learned to date on the risk relationship between cardiovascular disease and risk markers is predicated on the assumption that a risk maker of level X in a person on diet A is the same as it would be for a person on diet B.
Since virtually all of the thousands of subjects who have made up the dozens of studies that form the basis for our understanding on this topic were consuming some variant of the “standard American diet” (i.e., high-carb), it is quite possible that what we know about risk stratification is that this population is not entirely fit for extrapolation to a population on a radically different diet (e.g., a very-low carbohydrate diet or a ketogenic diet). Many of you have asked about this, and my comments have always been the same. It is entirely plausible that an elevated level of LDL-P or apoB in someone consuming a high-carb diet portends a greater risk than someone on a ketogenic or low-carb diet. There are many reasons why this might be the case, and there are many folks who have made compelling arguments for this hypothesis.

But we can’t forget the words of Thomas Henry Huxley, who said, “The great tragedy of science is the slaying of a beautiful hypothesis by an ugly fact.” Science is full of beautiful hypothesis slayed by ugly facts. Only time will tell if this hypothesis ends up in that same graveyard, or changes the way we think about lipoproteins and atherosclerosis.

The role of sugar in cardiovascular disease

Let’s start with what we know, then fill in the connections, with the goal of creating an eating strategy for those most interested in delaying the onset of cardiovascular disease.

There are several short-term studies that have carefully examined the impact of sugar, specifically, on cardiovascular risk markers. Let’s examine one of them closely. In 2011 Peter Havel and colleagues published a study titled Consumption of fructose and HFCS increases postprandial triglycerides, LDL-C, and apoB in young men and women. If you don’t have access to this journal, you can read the study here in pre-publication form. This was a randomized trial with 3 parallel arms (no cross-over). The 3 groups consumed an isocaloric diet (to individual baseline characteristics) consisting of 55% carbohydrate, 15% protein, and 30% fat. The difference between the 3 groups was in the form of their carbohydrates.

Group 1: received 25% of their total energy in the form of glucose
Group 2: received 25% of their total energy in the form of fructose
Group 3: received 25% of their total energy in the form of high fructose corn syrup (55% fructose, 45% glucose)

The intervention was relatively short, consisting of both an inpatient and outpatient period, and is described in the methodology section.

Keep in mind, 25% of total energy in the form of sugar is not as extreme as you might think. For a person consuming 2,400 kcal/day this amounts to about 120 pounds/year of sugar, which is slightly below the average consumption of annual sugar in the United States. In that sense, the subjects in Group 3 can be viewed as the “control” for the U.S. population, and Group 1 can be viewed as an intervention group for what happens when you do nothing more in your diet than remove sugar, which was the first dietary intervention I made in 2009.

Despite the short duration of this study and the relatively small number of subjects (16 per group), the differences brought on by the interventions were significant. The figure below shows the changes in serum triglycerides via 3 different ways of measuring them. Figure A shows the difference in 24-hour total levels (i.e., the area under the curve for serial measurements – hey, there’s our integral function again!). Figure B shows late evening (post-prandial) differences. Figure C shows the overall change in fasting triglyceride level from baseline (where sugar intake was limited for 2 weeks and carbohydrate consumption consisted only of complex carbohydrates).
impact on TG
The differences were striking. The group that had all fructose and HFCS removed from their diet, despite still ingesting 55% of their total intake in the form of non-sugar carbohydrates, experienced a decline in total TG (Figure A, which represents the daily integral of plasma TG levels, or AUC). However, that same group experienced the greatest increase in fasting TG levels (Figure C). Post-prandial TG levels were elevated in all groups, but significantly higher in the fructose and HFCS groups (Figure B). The question this begs, of course, is which of these measurements is most predictive of risk?

Historically, fasting levels of TG are used as the basis of risk profiling (Figure C), and according to this metric glucose consumption appears even worse than fructose or HFCS. However, recent evidence suggests that post-prandial levels of TG (Figure B) are a more accurate way to assess atherosclerotic risk, as seen here, here, and here. One question I have is why did the AUC calculations in Figure A show a reduction in plasma TG level for the glucose group?

The figure below summarizes the differences in LDL-C, non-HDL-C, apoB, and apoB/apoA-I.
impact on lipoproteins
Again, the results were unmistakable with respect to the impact of fructose and HFCS on lipoproteins, and by extension, the relative lack of harm brought on by glucose in isolation. [Of course, removal of glucose and fructose/HFCS would have been a very interesting control group.]
One of the simultaneous strengths and weaknesses of this study was the heterogeneity of its subjects, who ranged in BMI from 18 to 35, in age from18 to 40, and in gender. While this provided at least one interesting example of age-related differences in carbohydrate metabolism (older subjects had a greater increase in triglycerides in response to glucose than younger subjects), it may have actually diluted the results. There were also significant differences between genders in the glucose group.
What was most interesting about this study was the clear difference between the 3 groups that was not solely a function of fructose load. In other words, the best outcome from a disease risk standpoint was in the glucose group, while the worst outcome was not in the all-fructose group, but in the 50/50 (technically 55/45) mixed group. This is a very powerful indication that while glucose and fructose alone can be deleterious in excess, their combination seems synergistically bad.

The role of saturated fat in cardiovascular disease

In the next week or two I’ll be posting an hour-long comprehensive lecture I gave at UCSD a few weeks ago on this exact topic. Rather than repeat any of it here, I’ll highlight one study that I did not include in that lecture. The study, Effect of a high saturated fat and no-starch diet on serum lipid subfractions in patients with documented atherosclerotic cardiovascular disease, published in 2003, treated 23 obese patients (average BMI 39) with known cardiovascular disease (status post coronary artery bypass surgery and/or stent placement) with a high-fat ketogenic diet. Because the study was free-living and relied on self-reporting, not all subjects had documented levels of elevated serum B-OHB. However, the subjects were instructed to avoid starch and consume 50% of their caloric intake via saturated fat, primarily in the form of red meat and cheese. There were no restrictions on fruits and vegetables, which may have accounted for the observation that not all subjects were ketotic during the 6-week intervention. In total, only 5 of the 23 patients achieved documented ketosis.
All of the subjects were on statins and entered the study at a goal LDL-C level target of 100 mg/dL, which may have been the only way the authors could get the IRB to approve such a study.
The table below shows the changes in lipoprotein fractions following the intervention (there was no control group):
Table 2
This study was conducted during the height of the “outcry” over the Atkins diet. While most doctors reluctantly agreed that Dr. Atkins’ diet could reduce body fat, most believed it was still very dangerous. In the words of Dean Ornish, “Sure you can lose weight on a low-carb diet, but you can also lose weight on heroin and no one would recommend that!”

Fair point. In fact, the authors of this study acknowledged that they “strongly expected” this dietary intervention to increase risk for cardiovascular disease, which is why they only included subjects on statins with low LDL-C. However, as you can see from the table above, the authors were startled by the results. The subjects experienced a significant reduction in plasma triglycerides and VLDL triglycerides, without an increase in LDL-C or LDL-P. In fact, LDL size and HDL size increased and VLDL size decreased – all signs of improved insulin resistance. Furthermore, fasting glucose and insulin levels also decreased significantly. The mean HOMA-IR was reduced from 5.6 to 3.6 (normal is 1.0) and TG/HDL-C from 3.3 to 2.0 (normal is considered below 3, but “ideal” is probably below 1.0) in just 6 weeks. Taken together, these changes, combined with the dramatic change in VLDL size, suggest insulin resistance was dramatically improved while consuming a diet of 50% saturated fat!

As all of these patients were taking statins, we’re really robbed of seeing the impact of this diet on LDL-P, which did not change. Also, CRP levels rose (though not clinically or statistically significantly).

Putting it all together

It is very difficult to make the case that when carbohydrates in general, and sugars in particular, are removed or greatly reduced in the diet, insulin resistance is not improved, even in the presence of high amounts of saturated fats. When insulin resistance improves (i.e., as we become more insulin sensitive), we are less likely to have the signs and symptoms of metabolic syndrome. As we meet fewer criteria of metabolic syndrome, our risk of not only heart disease, but also stroke, cancer, diabetes, and Alzheimer’s disease goes down.

Furthermore, as this study on the Framingham cohort showed us, the more criteria you have along the spectrum of metabolic syndrome, the more difficult it becomes to predict your risk, due to a widening gap in discordant risk markers, as shown in this figure.
LDL-C vs. LDL-P in MS
As I noted at the outset, the “dream” trial has not yet been done, though we (NuSI) plan to change that. Until then each of us has to make a decision several times every day about what we will and won’t put in our mouths. Much of this blog is dedicated to underscoring the impact of carbohydrate reduction on insulin resistance and metabolic syndrome.

The results of the trials to date, combined with a nuanced understanding of the lipoprotein physiology and their role on the atherosclerotic disease process, bring us to the following conclusions:
  1. The consumption of sugar (sucrose, high fructose corn syrup) increases plasma levels of triglycerides, VLDL and apoB, and reduces plasma levels of HDL-C and apoA-I.
  2. The removal of sugar reverses each of these.
  3. The consumption of fructose alone, though likely in dose-dependent fashion, has a similar, though perhaps less harmful, impact as that of fructose and glucose combined (i.e., sugar).
  4. The addition of fat, in the absence of sugar and starch, does not raise serum triglycerides or other biomarkers of cardiovascular disease.
  5. The higher the level of serum triglycerides, the greater the likelihood of discordance between LDL-C and LDL-P (and apoB).
  6. The greater the number (from 0 to 5) of inclusion criteria for metabolic syndrome, the greater the likelihood of discordance between LDL-C and LDL-P (and apoB).
I would like to address one additional topic in this series before wrapping it up – the role of pharmacologic intervention in the treatment and prevention of atherosclerotic disease, so please hold off on questions pertaining to this topic for now.

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Read the complete article here.

Wednesday, December 5, 2012

Dr William Davis was interviewed on the Dr Oz show

Cardiologist, Track Your Plaque founder and Wheat Belly author Dr William Davis was interviewed on the Dr Oz show tagged 'Are You Addicted to Wheat' on Monday Dec 3 2012. The complete show can be seen in three parts here.

http://www.doctoroz.com/episode/are-you-addicted-wheat

Monday, December 3, 2012

Cholesterol & heart disease – there is a relationship - Zoë Harcombe

Cholesterol & heart disease – there is a relationship, but it’s not what you think

I do a fortnightly newsletter called “Diet & Health Today” in our on line support club. The club is there to help people to lose weight by eating food – real food! Apparently that makes us radical and controversial. The main article in Diet & Health Today is called “The Big Issues” and we have tackled things from “how we have misapplied thermodynamics to weight loss” to “what role does exercise play in losing weight”.

This is a copy of possibly one of the most serious Diet & Health Today articles that I may do. It is dedicated to Anne (Annem in the club) who asked me a great question about cholesterol. It made me do what I had been meaning to do ever since I read Dr Malcolm Kendrick’s The Great Cholesterol Con

Dr MK ran some analysis on World Health Organisation (WHO) data. The WHO has extensive data from almost 200 countries on more health measures than you could imagine – definitely worth a look one rainy, wintry afternoon. This is where Dr MK presented the world with two different Seven Country Studies – (for those of you who aren’t familiar with the history, it was the Ancel Keys’ Seven Countries Study that started all the fat heart hypothesis stuff). Dr MK took the seven countries with the lowest saturated fat intake and then the seven countries with the highest saturated fat intake. You may need to read this twice – but he found: “Every single one of the seven countries with the lowest saturated fat consumption has significantly higher rates of heart disease than every single one of the countries with the highest saturated fat consumption.”

The next chapter in The Great Cholesterol Con goes on to look at cholesterol and heart disease (and overall death rates) and quotes many great studies where it is shown that lower cholesterol is associated with higher mortality. However, it did leave me thinking – having run the data on saturated fat and heart disease, let’s just run all the data on the cholesterol and heart disease and get to the bottom of this hypothesis from all parts of the allegations.

It actually didn’t take that long – less than a couple of hours one Saturday afternoon. You go to the WHO statistics area of their web site and then pick data for cholesterol from risk factors (how judgemental to start with!) and then look under: Global burden of disease (mortality); All causes; Non communicable diseases and then G Cardiovascular disease (shortened to CVD). CVD deaths include ischemic heart disease and cerebrovascular disease – that means fatal heart attacks and fatal strokes to us. You find the most recent year where you can get both sets of data to compare like with like. This turns out to be 2002. You download their very user friendly spreadsheet data (CSV) – cut and paste it into an excel file and then try to remember how the heck to do scatter diagrams in excel!
Before telling you the results, we need to go back for a quick reminder on what we know about cholesterol and then hopefully this can serve as a factsheet for all the cholesterol questions we continually get.
 
The role of cholesterol
It is virtually impossible to explain how vital cholesterol is to the human body. If you had no cholesterol in your body you would be dead. Every single cell of your body is covered by a membrane (think of a membrane as the ‘skin’ or protective barrier around each cell). This membrane is made largely of cholesterol, fat and protein. Membranes are porous structures, not solid walls, letting nutrients and hormones in while keeping waste and toxins out. If cholesterol were removed from cell membranes they would literally explode from their internal water pressure. Human beings quite simply die without cholesterol.

Cholesterol is vital for hormone production – the sex hormones and therefore the entire human reproductive system are totally dependent on cholesterol. Hence, not only would humans die without cholesterol, the human race would die out.

Cholesterol is vital for digestion. The human body uses cholesterol to synthesise bile acids. Without cholesterol-rich, bile salts, the human body could not absorb essential fatty acids or the fat soluble vitamins (A, D, E and K) and serious, even life threatening, deficiencies could develop. (It is interesting, therefore, that nature puts cholesterol in virtually every food that contains fat – providing a digestion mechanism in tandem).

Cholesterol is vital for the brain, central nervous system and memory functions (hence how the side effects of statins include memory loss, mental confusion and people generally just not feeling themselves). Even though the brain is only 2% of the body’s weight, it contains approximately 25% of the body’s cholesterol. The vital connections between nerve endings in the brain, which help to conduct the electrical impulses that make movement, sensation, thinking, learning, and remembering possible, are largely made up of cholesterol.

Cholesterol is critical for bones and for all the roles performed by vitamin D. Vitamin D is best known for its role in calcium and phosphorus metabolism, and thus bone health, but we are continually learning more about potential additional health benefits of vitamin D from mental health to immune health. Vitamin D can be ingested (and is, interestingly again, found in foods high in cholesterol) and it can be made from skin cholesterol. Modern ‘health’ advice to avoid the sun, take cholesterol-lowering drugs, eat a low cholesterol diet (whatever the heck that is supposed to be) – combined with there not even being a recommended dietary allowance for vitamin D – is undoubtedly contributing to avoidable modern illness.

One of the key reasons that we need to spend approximately one third of our lives sleeping is to give the body time to produce cholesterol, repair cells and perform other essential maintenance.
This gives you the headlines of the vital functions that cholesterol performs, but hang on to that bottom line – it is utterly vital and we die instantly without it.

You may be familiar with the term essential fatty acids or essential amino acids (proteins break down into amino acids). The term ‘essential’ used like this in nutrition means that it is essential that we consume it in our diet because the body can’t make it. The body makes cholesterol. That says to me that cholesterol is even more vital than essential fatty acids or essential amino acids – even though these too are life critical – and therefore the design of the human body is such that it was not left to chance that we needed to get cholesterol from food. Of the 500 or so roles that the liver has – one is to produce cholesterol. It is too vital to be left to chance.
 
What went wrong?
So, how did something so life vital become more vilified than a mass murderer? I think it comes down to three things (and I don’t take credit for this view – it is there to be worked out by anyone who traces back the history and Kendrick, Uffe Ravnskov and all the thincs.org guys have led the way):
1) Rabbits;
2) Ancel Keys;
3) Money!

1) In 1913, a Russian chap called Nikolai Anitschkow decided to feed rabbits purified cholesterol and he managed to get their blood cholesterol levels in excess of 1,000 mg/dl (nearly 26 mmol/L! Most UK people have levels of 5-7 mmol/L). He then noticed the formation of “vascular lesions closely resembling those of human atherosclerosis” forming in the arteries of the rabbits. The obvious flaw in the experiment should have been that rabbits are strict herbivores. They do not eat animal products, which is the only source of cholesterol. Hence rabbits are in no way designed to digest cholesterol or animal fat and no one should be surprised if cholesterol or animal fat ended up stuck in any part of the poor rabbit. The only surprise is that no one thought to ask Anitschkow why he was feeding cholesterol and animal fat to herbivores. Interestingly, far less well known is that a parallel test was done on rats and dogs (omnivores) and feeding cholesterol to these species failed to produce lesions.

2) Ancel Keys. Remember the Minnesota experiment that I so often refer to? A brilliant and unbiased piece of research, which has given the world one of the best insights into low calorie dieting ever done – it was pure genius. This study made Ancel Keys the man of the moment and I guess he wanted to follow it with something equally impactful. There is an anecdote in The Great Cholesterol Con and on p113 of The Obesity Epidemic where Henry Blackburn, one of Keys’ closest colleagues, tries to explain what may have fuelled Keys drive to find a connection between diet and heart disease.
What is little known is that Keys originally tried to establish a link between cholesterol in food and cholesterol in the blood (our cholesterol levels when we have a blood test) because he thought (probably because of poor Bugs Bunny) that cholesterol in the blood causes heart disease.

Keys did multiples of studies, changing the diets of his human ‘guinea pigs’, and he presented his conclusions in The Journal of Nutrition, November 1955: “It is concluded that in adult men the serum cholesterol level is essentially independent of the cholesterol intake over the whole range of natural human diets. It is probable that infants, children and women are similar.” i.e. I only tested adult men and there is no relationship between cholesterol eaten and cholesterol in the blood and it is probable that there will similarly be no relationship for women or children.

In 1997 Keys put this even more assertively: “There’s no connection whatsoever between cholesterol in food and cholesterol in blood. And we’ve known that all along. Cholesterol in the diet doesn’t matter at all unless you happen to be a chicken or a rabbit.”

Did you know – even the UK Food Standards Agency (FSA) and UK National Health Service (NHS) admit this?

- “However, dietary cholesterol has little effect on blood cholesterol. More important is the amount of saturated fat in your diet”. (National Health Service). (Notice the second sentence? They just couldn’t let the theory go).
- “But the cholesterol we get from our food has much less effect on the level of cholesterol in our blood than the amount of saturated fat we eat”. (Food Standards Agency). (This link may disappear, as the FSA is bowing out of giving nutritional advice).

What the government advice should say is: The body makes cholesterol. The cholesterol you eat has no impact on the level of cholesterol in your blood – not “little”, but “no” – (and we’ve known that all along). And they should also explain how saturated fat can determine blood cholesterol levels and then provide irrefutable evidence that it does. But it must be hard for public health bodies to even go this far. As we saw in a recent thread – the FSA also now accept that there is no limit on the number of eggs we can eat:

 

If only Keys had stopped here, but he wanted to find an explanation for heart disease and he was not about to be deterred. For some reason, which I find inexplicable, he then turned to fat (the entire literature on this topic is very vague about “fat” vs. “saturated fat” so his early writings are also very vague on the topic). Here’s a bit of Mensa logic for those who like this kind of thing:

i) Only animal foods contain cholesterol (meat, fish, eggs, dairy). NO non animal foods contain cholesterol.
ii) All animal foods contain fat – saturated and unsaturated. Some may be very low in fat (e.g. white fish), but they all contain some fat.
iii) If there is no link whatsoever between increased consumption of foods containing cholesterol and blood cholesterol levels, there can be no link whatsoever between increased consumption of animal foods and blood cholesterol levels since only animal foods can be increased in consumption to increase consumption of cholesterol!

So, Keys first did the graph that was presented at the Mount Sinai hospital (which is the one shown in the Tom Naughton video and in Dr Robert Lustig’s “Sugar: The Bitter Truth” ) and then went on to do the Seven Countries study – which I have read all twenty volumes of and take apart piece by piece in Chapter Eight of The Obesity Epidemic: What caused it? How can we stop it (on this page).
As Kendrick’s two unbiased seven country studies showed – there is not even an association between saturated fat and heart disease – let alone a causation. However, Keys published his seven countries study and the rest, as they say, is history.

3) The Robert Redford film All the Presidents’ Men that had the memorable quote “follow the money”. This is absolutely at the heart of everything in the diet industry from national dietary organisations to the food, drink and drug industries and individuals in between.

The Ancel Keys work interestingly claimed that saturated fat consumption (A) caused heart disease (C) not directly, but by raising cholesterol (B). Hence A was supposed to cause C through B. For this to even get off the starting blocks, A and C have to be related (plot one against the other and there has to be a clear relationship); A and B have to be related and B and C have to be related. None of these in fact holds. The Kendrick study shows that A and C are not related. There is no logic that A and B could be related – because of the problem of fat and cholesterol being found in the same foods and Kendrick presented many studies that showed B and C were not related. I aim in this article to put the nail in the coffin for any idea that high cholesterol is even associated with high heart disease. We will, in fact, show that the evidence confirms the opposite.

By having cholesterol as this middle-man, this has allowed an entire pharmaceutical industry (and stupid cook books) to come up with ways of lowering cholesterol. The most lucrative of these has clearly been statins – drugs designed to stop the body producing the cholesterol that it is designed to produce. It never hurts to remind people that one statin alone, Lipitor, has been worth $125 billion to Pfizer since 1997. Taubes has a deeply troubling passage in The Diet Delusion where he looked at the committee who approved a lowering of the target cholesterol levels for the USA population. From memory (it’s a big book to find a reference!), a number of people were on the committee and all but one were funded by pharma companies and one didn’t want the target cholesterol level lowered. I wonder which one! (Anyone reading this – if you can find the page number I’d be so grateful – my copy has so many scribbles on I can barely read it).

So, cholesterol will remain the mass murderer for as long as statins are as lucrative as they are or until the public are enlightened and courageous enough to say no to doctors who try to put them on this medication (like my mum was after reading Dr MK!)
 
A small technicality
On p35 of The Great Cholesterol Con, Kendrick says: “How can eating saturated fat raise LDL levels? It is not merely biologically implausible, it is biologically impossible. Boy does that statement make me a hostage to fortune!”

I arranged to meet a biochemist at a local university to try to get to the bottom of this statement. The biochemist (who has more qualifications than I’ve had dark chocolate) was sadly so brainwashed in the ‘fat is bad’ theory that he just kept saying eating fat raises cholesterol. When I asked him to talk me through the biochemical pathway from fat digestion through to how this impacts cholesterol he said he didn’t know the digestive process well enough – we would need to add a dietician into the conversation. This was alarming enough. I then said – we eat 39 grams of butter per person per week in the UK and about 1.4 kilos of flour – didn’t he think it was more likely that the flour was making us fat and sick. He said it only took a drop of arsenic to kill us. I left shortly afterwards.

Kendrick has to be right (isn’t he always?) LDL (remember this is not cholesterol – it is a low density lipoprotein) is the left over from IDL (intermediate density lipoprotein), which is the left over from VLDL (very low density lipoprotein). VLDL is one of the measures you get in your blood cholesterol test (actually they estimate it – they don’t measure it – they only measure total cholesterol and HDL leaving two other unknowns in an equation with four variables and you thought this was scientific). (They also call VLDL ‘triglyceride’, which is confusing and unhelpful). Cutting a complex story short (it is explained in my book in different passages), carbohydrates can impact VLDL levels (starter for 10: Acetyl-CoA being the start of the process by which the body makes cholesterol and part of the Kreb’s cycle whereby the body turns glucose into ATP), but I really have found no way in which the fat that we eat can do so. Because fat is not water soluble, it is packaged into a lipoprotein in the digestive system. The lipoprotein that fat goes into is the biggest one – the chylomicron – and then it travels off into the body to go and do the essential repair and maintenance jobs that fat does. Does the fat say – hang on Mr chylomicron – we need to go via the liver and see if we can mess up the body’s VLDL production in some way?! Do ask this ‘how’ question (in detail) of someone who thinks that this is possible. I am still open to someone answering this, but I’m not holding my breath.
Fructose, on the other hand, we do know goes straight to the liver to be metabolised. Could that, and other carbs, impact VLDL production? The evidence I have already seen is strong that they do.
 
The serious bit
The WHO data is split into men and women. I first did the scatter diagrams for average (mean) cholesterol levels and CVD deaths. Then I ran the Pearson correlation coefficient on these numbers. This gives us the term called “r”. “r” tells us if there is some kind of a relationship: an r score of 0 would indicate no relationship; an r score of 1 would indicate a perfect relationship. A negative r score is called an inverse relationship e.g. the price of concert tickets is likely to be inversely related to the number of concert tickets bought – fewer tickets being bought at higher prices.

The “r” score for men revealed that there was a small relationship of 0.13 – however this relationship was inverse. The diagram and correlation shows that higher cholesterol levels are associated with lower CVD deaths and lower cholesterol levels are associated with higher CVD deaths. In women, the relationship is stronger – to the point of being meaningful. The r score was 0.52 – but, again, inverse. For women, higher cholesterol levels are quite significantly associated with lower CVD deaths and lower cholesterol levels are quite significantly associated with higher CVD deaths. Please note that I have added r squared on the graphs below (excel can do this for us) and it can confirm that you’ve got your r numbers right and r squared tells us the strength of any relationship we have observed.

All you need to do is to look at the lines going down to the right and wonder how on earth we ever got away with telling people that cholesterol causes heart disease. High cholesterol is associated with lower heart disease and vice versa – for all the data available in the world. High cholesterol is not even associated with high heart disease, let alone does it cause it.


It gets worse. I then kept the cholesterol information and changed the death rates to total deaths – all deaths from any cause – cancer, heart disease, diabetes, strokes – all deaths. You can see the diagrams for men and women again below. This time there is a significant relationship for both men and women: 0.66 for men and 0.74 for women – again inverse. There is a significant association between higher cholesterol levels and lower deaths and lower cholesterol levels and higher deaths for men and an even more significant relationship for women.



This is serious. I’ve shown it to a couple of academics (Professor sort of things) with whom I’ve been having great debates, as I want to see what the view is from people who wholly believe the fat/cholesterol/heart/death hypothesis. (Kendrick talks in his book about what happened when he showed an intelligent colleague his two seven countries studies and the evidence was just dismissed instantly). It is most useful to know what the resistance arguments will be before starting to invite the resistance. The two arguments I got back were:

1) “Ah yes – but this is only an association.”
Ah yes – but a) we changed global dietary advice back in 1977-1983 on the back of an association in Seven (carefully hand picked) Countries that miraculously became a causation even when the association was far from established and b) it is an association that’s the opposite to the one that the world currently holds true and c) that’s what epidemiology is supposed to be about – establish an association and then investigate if there could be any causation or useful learnings. So – go out with a new paradox – that high cholesterol is associated with low deaths and then see what dietary advice emerges.

2) “But that’s total cholesterol – the key thing is the ratio of good to bad cholesterol.”
Oh boy! The chemical formula for cholesterol is C27H46O. There is no good version or bad version. HDL and LDL are not even cholesterol, let alone good cholesterol or bad cholesterol. They are lipoproteins – see above – and they carry cholesterol, triglyceride, phospholipids and protein. Do you think that taxis are people? Or do you think that they are carriers of people (and luggage, and pets and fresh air and other things).

Back to – this is serious. Why are we lowering cholesterol when lower cholesterol is associated with more deaths from heart disease and all causes for men and women?
The doctors’ Hippocratic oath is “First do no harm”.

This also says to me – even though saturated fat has nothing to do with cholesterol, it doesn’t actually matter. Even if it did – cholesterol is only associated with CVD deaths in an inverse way. If fat did raise cholesterol – as public health officials like to claim – it could save lives! Please note I am always really careful with language in this area and never jump from association or relationship to causation. Someone may be in the bath and they may be singing – if we observe this in many cases, we may claim that there is an association. We cannot say that bathing causes singing or that singing causes bathing.

Our global dietary advice was changed in 1977 in the US and 1983 in the UK as a result of a biased study of seven handpicked counties. Had the data been available for the 192 countries we can analyse now, or had Keys even considered all the data that was available to him at the time (for France etc), our conclusion may have been that we need to protect cholesterol levels in the body. We may have realised that the last thing we should be trying to do is lowering cholesterol – unless we’re trying to lower life expectancy for some reason.

Zoë Harcombe
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Read the complete article here.