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Tag: LDL

The Great Misunderstood High-Density Lipoprotein

What do I mean by “misunderstood?” Look no further than the common misnomer of “good” or “bad” cholesterol.

Good and Bad Cholesterol

While it may be true that High-Density Lipoprotein (HDL) has potentially beneficial functions (reverse cholesterol transport), we have to remember there is no such thing as good and bad cholesterol. The cholesterol carried by HDL is the same as that carried by LDL. The only thing that makes it good or bad is if it ends up synthesizing our hormones or bile acids (good), or if it ends up in our vessel walls (bad).

If it’s true there is no such thing as good and bad cholesterol, why do we care about our HDL levels?

First, let’s start with the basics.

HDL is the smallest and most densely packed lipoprotein and has one or more ApoA protein on its surface. HDL can help lipids move around in circulation by accepting triglycerides or cholesterol from other particles, thus helping a VLDL turn into an LDL, or helping an LDL contain less cholesterol (turning a small dense LDL into a less densely packed LDL).

Like LDL, HDL transports cholesterol to the liver for recycling or excretion, or to the hormone producing cells like in the adrenals. Unlike LDL, HDL does not have the potential to get retained in the vascular wall and does not, therefore, contribute to plaque formation. In fact, functioning HDL can remove cholesterol from the vessel wall, thus putting it back into circulation and possibly removing it from the body.

Back to the question at hand.

 

Why should we care about HDL levels?

Early epidemiological trials showed that lower HDL levels were associated with a higher risk of cardiovascular disease and even death.  With such a strong association, the medical profession promoted elevated HDL levels as protective and low levels as something we need to avoid.

Since these were observational epidemiological studies, they do not prove that the low HDL caused the problems, only that HDL was associated with it. For instance, HDL is also known to be low in diabetes, metabolic syndrome and insulin resistance. It may, therefore, simply be a marker of underlying metabolic dysfunction that contributes to increased risk.  Yet, HDL’s function in reverse cholesterol transport, and its ability to remove cholesterol from vessel walls suggests a more direct impact on cardiovascular health.

It is also important to note that the Framingham data suggested that increased cardiovascular risk with elevated total cholesterol and LDL-C was lost in the presence of high HDL. In fact, very low levels of LDL combined with very low HDL levels had a much higher risk than markedly elevated LDL levels when combined with elevated HDL.

Thus, HDL proves to be a useful marker to help predict cardiovascular risk. For instance, one large meta-analysis showed that total cholesterol/HDL ratio was a much stronger predictor of cardiac mortality than total cholesterol alone.

In addition, the PURE study, an observational trial in over 135,000 subjects, showed that when considering lipid changes brought about by nutritional changes, ApoB/ApoA1 (essentially LDL-P/HDL-P ratio) is the best predictor of clinical outcomes.

Thus, HDL level is important in assessing cardiovascular risk.

 

Drugs Muddy the Picture

While HDL may be a good predictor of risk, raising it with drugs does not seem to confer added benefit.

For instance, cholesterol ester transferase protein inhibitors (CETP inhibitors) significantly reduced LDL by 20-30% and increased HDL 100-fold, yet showed either no clinical benefit or even worse, an increased risk of death.

This was a shock to many in the lipid world as the notion of “good” and “bad” cholesterol would clearly predict lowering LDL and raising HDL would confer dramatic health benefits. So much so, that multiple pharmaceutical companies invested hundreds of millions of dollars developing these drugs only to abandon them when the trials showed no benefit.

Part of the issue is that not all HDL lipoproteins function the same. There are subsets of people with genetically determined markedly elevated HDL levels who have an increased risk of CVD. They may have plenty of cholesterol circulating in HDL particles, but the HDL particles are dysfunctional and therefore  do not effectively remove cholesterol from vessel walls or LDL and do not effectively transport it to the liver. Conversely, there are those with a specific genetic mutation called ApoA1 Milano who have very low HDL-C and lower cardiovascular risk.

Simply measuring the HDL cholesterol content, therefore, may not accurately reflect its function. While we do not have easily available tests to measure HDL function, we can potentially use HDL particle assessment as well as the company it keeps (i.e. low triglycerides, larger less dense LDL particles) to better assess the potential benefits of HDL. Thus, if there is any concern about potentially dysfunctional HDL, I usually recommend advanced lipid testing to see the specific subtypes of HDL.

What can we conclude from all the HDL confusion?

Raising HDL with drugs does not reduce cardiovascular events, yet having a naturally low HDL is associated with increased risk.

The best answer, therefore, is to live a lifestyle that helps you have a “not low” HDL level. This means first and foremost avoiding the medical conditions associated with low HDL (i.e. insulin resistance, diabetes, and metabolic syndrome).

Textbooks predictably state the interventions to naturally raise HDL include exercise and moderate alcohol intake. Unfortunately, these have minimal effects. In fact, they pale in comparison to a low carb high fat lifestyle. In my 20+ years in the medical field, I have never seen an intervention as effective as LCHF in raising HDL, and the studies agree.

This brings us back to our question once again.

Why are HDL levels important?

HDL levels are important because it is a reflection of our underlying metabolic health and our lifestyle. A properly constructed LCHF lifestyle lowers triglycerides, raises HDL, and reduces the small dense LDL, among other benefits. Such a lifestyle likely reduces overall cardiovascular risk and will likely be shown to improve longevity and health span. While HDL may not be the main reason for this, we can’t ignore its role simply because it is more nuanced than “good” and “bad” cholesterol.

My advice, therefore, is to see the whole picture. Embrace the nuance. And make sure you get a thorough and proper evaluation of your cardiovascular risk.

If you are hungry for more, I created my Truth About Lipids program, a program focused on Cholesterol, to help break through the confusion and provide you with everything you need to thoroughly understand cholesterol and its impact on your health.

Learn more: Truth About Lipids Program

 

If you still have questions, you may want to consider a one-on-one health coaching consultation so you can get the individual attention you deserve  with a thorough assessment of your lifestyle and its impact on you as an individual.

Please comment below if you have any questions or comments that may help further the discussion.

Thanks for reading.

Bret Scher MD FACC

High LDL cholesterol may protect against dementia – don’t tell the statin pushers!

Don’t tell the statin brigade, but elevated LDL cholesterol may actually help us as we age!

A new study from China suggests that those with higher levels of LDL-C have a lower incidence of dementia. They evaluated 3,800 subjects with a mean age of 69 years, performing extensive neuropsychological and cognitive ability testing. They found that the diagnosis of dementia and cognitive impairment correlated with increasing age, decreasing education level, diagnosis of type 2 diabetes, and being an ApoE4 carrier. After controlling for all these factors, they also found that those in the highest tertile of LDL-C (>142 mg/dL or 3.7 mmol/L) had a 50% lower incidence of dementia than those in the lowest tertile (<110 mg/dL or 2.9 mmol/L).

Frontiers in Neurology: High low-density lipoprotein cholesterol inversely relates to dementia in community-dwelling older adults: The Shanghai aging study

These findings are consistent with a prior study (also observational) examining the Framingham Heart Study data that found lower risk of dementia in those over 85 years old with higher cholesterol levels.

In fairness, these studies were observational studies, so they do not prove higher LDL-C directly protected against dementia. We can hypothesize why higher levels of LDL-C are associated with lower incidence of dementia. It could be a marker of overall health or nutritional status, it could be that LDL-C directly improves the health of neurons and prevents brain atrophy, or it could be more related to lack of diabetes or ApoE4 status for which a study may not always completely control.

Even without proving causation, these studies are wonderful reminders that we can easily get caught up in one specific disease processes (i.e. cardiovascular disease) and forget about the rest of the patient. The old joke is that when the surgeon talks to the family after a complicated and risky coronary bypass surgery, he says, “The surgery was a great success. The grafts were perfect, and the anastomosis were flawless, some of the best I have ever done. I’m sorry the patient died, but the surgery was wonderful.”

This is a fictional over-exaggeration, but it makes my point.

Cholesterol’s effects on our health are far too intricate to simply label LDL-C as “bad” and leave it at that. Such oversimplifications harm our overall understanding and eventually harms our health.

Instead, we need to focus on the whole patient, not one specific outcome. Trials should focus on all-cause mortality and overall morbidity rather than one or two specific outcomes. It doesn’t do us much good to lower heart attack risk by 0.5% over five years if we are also increasing the risk of dementia, cancer or other complications.

Thanks for reading,
Bret Scher MD FACC

 

Originally Posted on the Diet Doctor Blog 

Management of blood cholesterol just got personal

Don’t look now, but the updated clinical practice cholesterol guidelines from the American College of Cardiology, the American Heart Association and others are getting personal. Although the guidelines still contain their familiar approach — that I consider too aggressive with drug therapy — the latest 2018 version of the guidelines now includes an impressive update to emphasize lifestyle intervention, plus a more individualized approach for risk assessment.

MedPage Today: AHA: Revised Lipid Guide Boosts PCSK9s, Coronary Calcium Scans

Could this be the start of a progressive trend away from shotgun statin prescriptions? I sure hope so.

Prior guidelines emphasized the 10-year ASCVD risk calculator as the main determining factor for statin therapy. In the 2018 update, the guidelines acknowledge that the calculator frequently overestimates the risk in those individuals who are more involved with prevention and screening. (In other words, those patients more interested in and proactive about their health; I find many in the low-carb world fall into this category.)

The ensuing discussion with a healthcare provider should then focus on:

[T]he burden and severity of CVD risk factors, control of those other risk factors, the presence of risk-enhancing conditions, adherence to healthy lifestyle recommendations, the potential for ASCVD risk-reduction benefits from statins and antihypertensive drug therapy, and the potential for adverse effects and drug–drug interactions, as well as patient preferences regarding the use of medications for primary prevention… and the countervailing issues of the desire to avoid “medicalization” of preventable conditions and the burden or disutility of taking daily (or more frequent) medications.

I appreciate the attention the new guidelines bring to the depth of the discussion that should ensue between doctor and patient. Considering the treatment burden is equally as important as the burden of disease, and possibly even more important in patients who have not been diagnosed with heart disease, these individualized discussions about trade-offs are critical to personalized care.

Also worthy of mention is the increased use of coronary artery calcium scores (CAC) to help individualize risk stratification. The updated guidelines specify CAC may be useful for those age 40-75 with an intermediate 10-year calculated risk of 7.5%-20%, who after discussion with their physician are unsure about statin therapy. They specify that a CAC of zero would suggest a much lower risk than that calculated by the ASCVD risk formula, and thus take statins off the table as a beneficial treatment option.

This is huge. I cheered when I read this! I have been critical of prior guidelines that focused on ways to find more people to place on statins. The mention of finding individuals unlikely to benefit from statins is a giant step in the right direction.

The guidelines go even further: they mention that a CAC either over 100 or greater than the 75th percentile for age increases the CVD risk and the likely benefit of a statin. A CAC between 1-99 and less than the 75th percentile does not affect the risk calculation much and it may be worth following the CAC in five years in the absence of drug therapy. I would still argue that a CAC >100 does not automatically equal a statin prescription and we need to interpret it in context, but I greatly appreciate this attempt at a more personalized approach.

The guidelines also go beyond the limited risk factors included in the ASCVD calculator by introducing “risk modifying factors” such as:

  • Premature family history of CVD
  • Metabolic syndrome
  • Chronic kidney disease
  • Chronic inflammatory conditions such as rheumatoid arthritis and psoriasis
  • Elevated CRP > 2.0 mg/L
  • Elevated Lp(a) > 50 mg/dL or 125 nmol/L
  • Elevated triglycerides > 175 mg/dL

Although they use these criteria to define an increased risk, the opposite would likely hold true. An absence of those criteria could define a lower risk situation.

Some changes deserve mention from a controversy standpoint as well. For instance, the new guidelines recommend checking lipid levels as early as two years old in some circumstances. Two!

They also recommend statin therapy for just about everyone with diabetes with no mention of attempting to reverse diabetes before starting a statin, a drug that has been shown to worsen diabetes and insulin resistance. In addition, the new guidelines do not mention the likely discordance between LDL-C and LDL-P in those with diabetes.

Last, the new guidelines define an LDL-C > 190 mg/dL as an absolute indication for statin therapy with a treatment goal of 190 mg/dL is in familial hypercholesterolemia populations (and even then has heterogenous outcomes). There is a clear lack of data supporting that same recommendation for metabolically healthy individuals with no other cardiac risk factors and no other characteristics of familial hypercholesterolemia. This is a clear example of when a guideline turns from “evidence based” to “opinion based.”

In summary, the guideline committee deserves recognition for its emphasis on an individualized care approach, its use of CAC, and its broader description of discussing potential drawbacks of drug treatment. It still combines opinion with evidence and believes all elevated LDL is concerning, but I for one hope it will continue its progression away from generalizations and someday soon see that individual risk variations exist, even at elevated LDL-C levels.

Thanks for reading,
Bret Scher MD FACC

Originally Posted on the Diet Doctor Blog 

Low Carb LDL- A Call for Reason

Can we be certain that elevated LDL (Low-density lipoprotein) particles have no meaning and can be completely ignored?

 

Certainly not.

 

Can we be certain that all LDL particles are deadly and need to be treated to microscopically low levels?

 

Certainly not.

 

So, what do we do?

 

I have seen countless second opinion consults and enrolled numerous clients in my Boundless Health Program who have this exact question.  What’s the deal with LDL? Do we worry or don’t we?

 

Life is much easier when it is black and white, good and bad. I, however, believe in looking for the nuance and trying to understand things a little deeper.

 

But first, let’s back up a little.

 

What is LDL and LDL-P?

 

Cholesterol can be a complex topic that we frequently oversimplify, which I am about to do. In brief, LDL is known as the “bad” cholesterol, the cholesterol that is found in plaque buildup in our hearts. But the truth is that LDL is not inherently bad. In fact, LDL has a purpose in our bodies as part of our immune response and as a fuel and vitamin delivery mechanism to name a few.  If vascular injury and inflammation are present, then modified LDL may invade vessel walls and participate in a cascade of events leading to plaque buildup and an eventual heart attack.

 

LDL-C is a measure of the total amount of cholesterol in our LDL lipoproteins. LDL-P is the total number of the LDL lipoproteins. Studies show that LDL-P is a much better marker for CVD risk than LDL-C. As an analogy, the number of cars on the road matter more than the number of people in the cars.

 

What are the risks of LDL-P?

 

On the one hand, trials in the general population show that elevated LDL-P is a risk factor for cardiovascular disease (CVD).  This includes a combination of observational trials, genetic mutation trials (mendelian randomization), and drug treatment trials.

 

All things being equal, based on these trials alone, we should want our LDL-P to be low.

 

But does LDL alone cause heart attacks and death? Or are there other factors involved?

 

Of course there are other factors involved in CVD. Vascular injury and inflammation being the two most prominent factors.

 

Can lowering our LDL-P have risks greater than the potential benefits for certain populations?

 

Absolutely.  Since primary prevention statin trials show we have to treat over 200 people for five years to prevent one heart attack with no difference in mortality, it seems reasonable that certain populations will experience more potential risk than reward.

 

The Low Carb High Fat Reality

 

How many LDL or statin trials have specifically looked at individuals on a healthy, real foods, LCHF diet?

 

None. Not a single one.

 

How many LDL or statin studies have looked specifically at red headed, left handed boys born the second week of March? 

 

None, at least to the best of my knowledge.

 

This seems glib but bear with me.

 

Is there any reason to think a red headed, left handed boy born the second week of March would behave any differently than everyone else in these LDL studies? Not really. Especially if they are eating a standard American diet or a low -fat diet as was almost exclusively studied in every cholesterol or statin trial.

 

Here’s the more important question. Is there reason to believe individuals on a healthy, real foods, LCHF diet would behave any differently than everyone else in the decades of lipid and statin studies?

 

There absolutely is reason to believe they may behave differently. There is not clear proof, but there is plenty of reason to suspect it.

 

Think about the benefits of a LCHF lifestyle.

  • Lowers inflammation
  • Reverses insulin resistance
  • Naturally raises HDL and lowers TG
  • Converts majority of LDL particles to larger, more buoyant particles
  • Lowers blood pressure
  • Reduces visceral adiposity

Could these create an environment where an elevated LDL is less of a concern?

 

It sure could.

 

To be clear, I openly acknowledge that we do not have definitive proof that we should have no concern with LDL in this situation. In my opinion, this is a specific scenario that the existing trials simply do not address one way or the other.

 

So, it seems we have two choices.

 

  1. Since we don’t have any proof we can ignore LDL in this setting, we plug the numbers into the 10-year ASCVD calculator and start a statin if the risk is above 7.5%, or we ask the individual to change their lifestyle in hopes the LDL will come down.
  2. If the individual is enjoying multiple health benefits from their lifestyle, and they are rightly concerned about the potential risks of statin therapy, then we can follow them for any sign of vascular injury or plaque formation, or any worsening of their inflammatory markers or insulin sensitivity. In the absence of any potentially deleterious changes, we can reason that the risk is low, and the benefits of living the healthy lifestyle may outweigh the risks.

 

The “problem” is that the second option requires a detailed discussion of the risks and benefits. It requires close monitoring and follow up. It requires us to think outside general guidelines and consider everyone as an individual with their own unique circumstance. These are qualities that our current healthcare system sorely lacks.  Yet that is the exact care that each individual deserves.

 

What do we do in the meantime?

 

I hope someday soon we will have definitive long-term evidence that a high number of large buoyant LDL particles along with elevated HDL, low TG and low inflammatory markers is perfectly safe.

 

Until that day, we will have to continue to talk to our patients. To see them as individuals. To weigh the lifestyle benefits with the possible risks. That includes seeing the risks in real numbers- not quoting a 30% benefit with statin therapy. Instead, having a real discussion that statins may reduce your risk a heart attack by 0.6% with an increased risk of muscle aches, an increased risk of diabetes, and a potential increased risk for cognitive and neurological dysfunction.

 

And we will have to understand that the answer won’t be the same for each person. And we can be OK with that.

 

So, do you have to worry about your LDL? I don’t know. But I welcome the opportunity to explore the question and reach the best answer for you.

 

Do you have questions about what your lipids may mean for you? What they mean when taken in the context of your lifestyle and overall health picture? If so, you may want to learn more about my Health Coaching Consult.

Thanks for reading,

Bret Scher, MD FACC

What Does My Cholesterol Level Mean?

What Does My Cholesterol Level Mean?

 

Depending on how you look at it, cholesterol can be an incredibly simple topic, or an incredibly confusing one. Contemporary medicine teaches that cholesterol is “bad” and should be low.  That seems pretty simple, right? Get it tested, if it’s high start a drug to lower it. 

 

Times have changed. Now, cholesterol is much more complex, and we all need to be armed with knowledge before we sit down with our doctors to evaluate our cholesterol levels.

 

Here is my guide to you and your doctor for evaluating your cholesterol.

 

1. Understand the difference between Total Cholesterol (TC) and high density lipoprotein (HDL) and low density lipoprotein (LDL)

 

If you doctor is referring to your total cholesterol (TC) and is making decision based on your TC— Run, don’t walk. Run away and find another doctor. TC is comprised of low density lipoprotein (LDL), so-called “bad cholesterol” even though it isn’t bad. High density lipoprotein (HDL), so-called "good cholesterol", and remnant cholesterol (VLDL and IDL). Initial studies in the 1960s and 70s looked at TC and risk of cardiovascular disease (CVD) and found a weak association.  That was prior to when scientists learned how to measure LDL and HDL.

 

Studies then looked at the individual lipoproteins (i.e. LDL and HDL) and found the higher the LDL, in general, the higher the risk for CVD. And the higher the HDL< the lower the risk of CVD. So, while talking about TC was cutting edge in the 60s and 70s, it is woefully outdated today. That is why if your doctor is still evaluating and treating TC—Run!

 

2. Does Your Doctor Know Your TC to HDL and TG to HDL Ratios?

 

If your doctor does not know your ratios, this is another reason to run away and find another doctor (We are doing lots of running here, bonus exercise!) Studies in the early 2000s and more recently have shown that total cholesterol to HDL ratio (TC:HDL) and triglyceride to HDL ratio (TG:HDL) are BETTER predictors of cardiovascular risk than isolated LDL, TC or HDL.

 

By incorporating TG and HDL into the analysis, these ratios incorporate the impact of remnant cholesterol and track with insulin resistance, both strong predictors of CVD. These ratios are calculated from a standard lipid profile, so they do not require any special testing or special labs. They are widely available for everyone to see. So if your doctor is not using them to evaluate your lipids, it's time to find a new one.

 

3. Understanding a Familial hypercholesterolemia (FH) diagnosis

 

Familial hypercholesterolemia (FH) is a diagnosis that requires (wait for it…) a family history! As the name suggests, it is an inherited condition passed from generation to generation. All too often, doctors will see an LDL level over 190 and make the diagnosis of FH. If your doctor makes that diagnosis that based on level alone without a family history, run!

 

There is a well-accepted scoring system, The Simon Broome Criteria, to help determine if someone has FH. This equation factors in age of diagnosis, absolute level of LDL, in addition to family history of early onset hyperlipidemia or early onset heart disease. It makes a big difference if you have FH or not. Don’t let your doctor label you as having FH without applying the full criteria. Just wait for the look on their face when you respond, “What was my Broome score? Did it confirm I have FH?” and hope you don't hear crickets.

 

4. What is Advance Lipid Testing?

 

Advance lipid testing may be helpful. And it may not. Advanced lipid testing can tell us the size, density, and inflammatory characteristics of our lipoproteins. This can help further risk stratify the potential danger of our lipids. For instance, small, dense LDL tend to correlate more strongly with CVD, whereas so-called pattern A LDL (the larger, less dense version) does not correlate as well.

 

Here is the interesting part. Those with high TG and low HDL almost uniformly have small dense LDL and increased inflammation. Conversely, those with low TGs and high HDL have Pattern A, larger less dense LDL. Are you starting to see a pattern? Low TG and high HDL=good. High TG and low HDL=bad.

 

Sometimes, however, there can be variation in this equation. Therefore, I usually suggest people get advanced lipid testing one time to see if their results correlate. If they do, then you can just follow your ratios to predict your advanced results. Why not get them all the time? They are frequently not covered by insurance and can be expensive.

 

5. Interpret your lipids in context

 

Lipids don’t exist in a vacuum. They exist in your body, so it's important to take into account what else is going on in your body. Insulin resistance and inflammation can directly affect your lipids and increase your risk in general. Hypertension, obesity, and family history of heart disease also play crucial roles in determining your risk.

 

Therefore, if your doctor checks only your lipids and bases decision on those labs alone—Run! Instead, you should get a hsCRP, Hgb A1c, fasting glucose, insulin and HOMA-IR, BP measurement, family history assessment, and complete history. This is the context in which your lipids should be evaluated. Not alone in a vacuum.

 

6. Why test a risk factor that may be related to CVD risk when you can test the disease itself?

 

Good question, right? To truly know what your lipids mean to you, you also need to know if you have evidence of CVD. Coronary artery calcium scores and Carotid Intima Media Thickness (CIMT) are two easy, relatively inexpensive tests, that you can get to show you whether or not you have current evidence of CVD. The presence or absence of disease significantly impacts the risk of lipid levels.

 

So, What Does Your Cholesterol mean to You? It depends.

 

It depends on many factors, and only by evaluating ALL of those factors can you truly know what impact your lipids may be having on our health. Anything short of this evaluation is an inadequate and antiquated approach to lipids.

 

Now you are forewarned and forearmed, and you can walk into your doctor’s office ready to ask the important questions and help guide the workup so that you can know what your cholesterol means to you.

 

Thanks for reading, and as always, please let us know If you have any comments or questions.

 

Bret Scher MD FACC

Founder, Boundless Health

www.LowCarbCardiologist.com

 

Zero LDL vs Ketogenic Diet- Which Prevents Heart Disease?

Virta Health continues to revolutionize the treatment of diabetes. And they are doing it while taking drugs away!

 

They recently released their study of cardiovascular risk data which, no surprise to me, shows significant improvement in patients’ risk profile. This impressive lifestyle study contrasts sharply with the other side of the coin- promoting drugs to drive LDL to a near zero level in the hopes of helping patients. That’s the other study I read last week, and I was much less excited about it.

 

Two wildly different approaches with wildly different magnitude of benefit. Let’s dig deeper to learn more….

 

The Virta Health Study:

 

The Virta Health trial enrolled subjects with diabetes, mean age was 54 years old, and they were obese on average with a BMI 40.  After 1 year, they had the following results:

  • LDL particle number decreased by almost 5%,
  • Small LDL decreased by 20%,
  • Apo A1 increased by almost 10%,
  • TG decreased by 24%,
  • HDL increased by 18%,
  • TG/HDL radio decreased by almost 30%,  
  • Large VLDL particles decreased by 38%,
  • CRP decreased by almost 40%,
  • The 10-year calculated risk went down by 11% ,
  • No change in CIMT, and
  • LDL-C went up by 10%.

 

EVERYTHING IMPROVED! Except for a small increase in LDL-C.

 

The first question this study forces us to ask, therefore, is should we care about the LDL-C? That is the only marker that went “the wrong” way, increasing 10%. But that is in the face of the LDL-P decreasing, the size of the LDL improving, and dramatic improvements in HDL and TG. All things that are likely protective against CAD.

 

Going all the way back to Dr. Castulli and the Framingham data, we know that LDL-C is a very poor predictor of CVD in the setting on high HDL. We also know that markers such as LDL-P and non-HDL cholesterol are better predictors of CVD than LDL-C.

 

So, in short, the answer is no. We should not be concerned with a 10% increase in LDL-C in this setting.

 

The second question is this. Does this data show that one year on a ketogenic diet is BENEFICIAL for heart health?

 

The original assumption within the medical community was that a ketogenic diet would be harmful and lead us to our grave (as many docs still believe).

 

The times they are a changin.’

 

Based on this data, the question has changed significantly. We should no longer concern ourselves with wondering if a very low carbohydrate, ketogenic diet could be harmful. The data is overwhelming that it is not. Instead, we need to ask if this diet protects us from heart disease.

 

Of course, we would need long term outcome data to show us that for certain. But in the absence of that, the most recent Virta Health data provides a strong vote of confidence that a very low carbohydrate ketogenic diet is likely cardioprotective.

 

That is my kind of medical science. Showing that lifestyle changes promote health.  Clean and simple.

 

The Drug Trials- PCSK9i

 

The Virta Health study contrasts sharply with another paper I read recently, one that claims it is safe and beneficial to lower LDL as low as possible, the so called “Zero LDL hypothesis.”

 

I have to admit, I started reading with a heavy contrary bias. I wanted to rip it apart and find all the shortcomings in the paper.  There were plenty, but I also have to admit that there are some very well thought out and well-argued points.

 

The general argument is that statins and PCSK9i are able to lower LDL to extremely low levels without documented significant adverse effects thus far. Therefore, there is no “floor” for how low we should drive down LDL.

 

Both statins and PCSK9i work by increasing the efficacy of LDL receptors, but they allow other compensatory mechanisms to remain functioning. For instance, the authors describe “back up” mechanisms for maintaining neuronal health, hormone synthesis, and even vitamin E transport (all of which are theoretical concerns with lowering LDL). They argue, since the back-up systems prevent adverse outcomes, and PCSK9i studies have gotten LDL down to 30, we can therefore safely drive LDL down to zero.

 

That’s a stretch that remains to be proven. However, the main question they fail to answer is this: Is worth the effort?

 

Once again, we see studies generating a tremendous amount of publicity and praise for underwhelming and conflicting results. Here’s what I mean:

 

The first big trial with PCSK9i was called the FOURIER trial. They enrolled patients with known cardiovascular disease and added PCSK9i or placebo to their current care. After 2 years, the PCSK9i drug reduced LDL by 60% to a median level of 30mg/dl (lower than any other major trial). The results? There was a small decrease in non-fatal heart attacks (1.2%), with absolutely no improvement in mortality. It did not save a single life.

 

The second trial that got even more attention was the Odessey trial. They enrolled individuals with a recent cardiac event and added PCSK9i or placebo to their standard care. After 2.8 years they lowered LDL by 61% to an average level of 53mg/dl.  Again, there was a very small 1.5% reduction in a combined primary endpoint. In reality, this is negligible clinically even though it is statistically significant.

 

Where the trials differed, however, was that Odessey showed a very small reduction in all-cause mortality of 0.6%., whereas Fourier did not.

 

But here is where it gets complicated. What the press and mainstream cardiology societies don’t tell us is that because of the way the trial was structured, this is not a truly significant finding. It had a weakly positive p value, but since cardiac mortality was not decreased, it invalidated the all-cause mortality. Don’t worry. I don’t completely understand this part either. But I’m told that’s how statistics work in this case.

 

In summary, despite lowering LDL cholesterol to levels lower than we have even seen before with drug therapy, the benefits were underwhelming. If LDL was the true cause of heart disease, there should have been breath takingly dramatic benefits. Yet, one trial showed no improvement in all-cause mortality. One may have shown an improvement, but the trial can’t really claim that.

 

Yet somehow the conclusion is that now we should drive LDL down to zero.  Where did that come from????

 

First Do No Harm

 

The belief that we should drive ldl to zero with drugs comes from the inherent bias in modern medicine: When it comes to drug therapy, “more is better,” and drugs are the best choice for treatment.

 

After all, the trials “proved” that the drugs were safe with no significant increase in adverse effects, right?  Not so fast. Lack of side effects at 2 years is not very reassuring for a drug people will be on for decades. There is plenty of concern about long term effects of near zero LDL levels, even if the authors postulate ways the body will compensate.  To counteract that concern, the benefits better be monumental.

 

After all, the medical oath is “First do no harm”.  Not “First assume there will be no harm”.

 

And more importantly, just because we can treat LDL to near zero, doesn’t mean we should. If we aren’t helping people live longer or live better, then what are we accomplishing?

 

Instead of talking about zero LDLs, we should be talking more about Virta Health. They showed the ability to reverse one of the most common chronic diseases we face with simple lifestyle interventions. And they did it while improving cardiovascular risk factors and getting people off of their medications. In my eyes, that deserves a ticker tape parade.

 

My take home message: Lifestyle beats drugs. Commit to lifestyle change and the argument about reducing your LDL to zero is a non-factor.  

 

What’s your take home message? Let us know your thoughts or if you have questions at www.LowCarbCardiologist.com

 

Thanks for reading

 

Bret Scher, MD FACC

Founder, Boundless Health

www.LowCarbCardiolgist.com

PCSK9 inhibitors- Hype or Hope?

Hot off the presses, just published today in NEJM. The new drug class PCSK9 inhibitors reduce heart attacks by 15%. Should we all rush out and start on one? Not so fast.

 

Initial studies demonstrated that Repatha (a PCSK9 inhibitor) dramatically reduced LDL cholesterol levels, but now we have evidence that they reduce the risk of heart attacks. Get ready for the barrage of commercials and ads for Repatha, and get ready for the experts to start proclaiming the benefits of this drug.

 

But as always, the truth may not live up to the hype.

 

For starters, the FOURIER trial focused on high risk patients who have already had heart attacks or strokes, and who were already on statins. This is called a secondary prevention trial. It is crucial to point out that it was not a primary prevention trial. The results do not apply to the millions of people with cardiovascular risk factors who have never had a heart attack or stroke (or peripheral vascular disease).

 

Second, the study did not show any difference in cardiovascular deaths. This is another important point as people frequently equate heart attacks with death. That is not the case. There was absolutely no difference in the risk of dying between the Repatha group and the placebo group.

 

Third, the reduction in heart attacks, although statistically significant, was small. Over 2.2 years, the risk of heart attacks was reduced by 1.2%. That means we need to treat 66 people for over 2 years to prevent 1 heart attack. Another way to look at it is that 65 people will not get the end benefit, and one will.

 

Last, the study was only 2.2 years long. The risk of side effects was similar between the two groups, suggesting that PCSK9 inhibitors don’t cause any adverse effects beyond statins. However, this is likely a big question mark regarding these drugs. These drugs drive the LDL lower than any other medication we have ever had. In this study, the average LDL for the Repatha group was 30. Our goal used to be 100, then 70, and now apparently 30. That’s quite a drop.

 

Is there reason to believe an LDL this low could be dangerous? You bet. LDL, although commonly known is the “bad” cholesterol, is vital for our health. We need it for neurologic and cognitive function. We need it for hormone production. We need it for cell membranes and for absorbing fat soluble vitamins.

 

Are you satisfied that the drug is harmless after this 2.2-year study? Neither am I. Stay tuned for the discovery of significant adverse effects over the next few years.

So far, I haven't even mentioned cost. If the drug was free, it would still be questionable if it was worth taking. But the drug is most certainly not free. In fact, it costs $14,000 per year.

Since we need to treat 66 people for 2.2 years to prevent one heart attack, that makes it $2.03million per heart attack saved. <Cough> That's a tough pill to swallow.

 

So why are so many experts going to promote it and extol its benefits? Most physicians believe that medicines are the path to health. The more we can alter our natural environment with drugs the better. Even minimal reductions in our risk are worth the minimal side effects from drugs. That seems to be a common bias in our healthcare system.

 

My bias is the exact opposite. We can achieve incredible benefits from purposeful lifestyle changes, and all without adverse effects! Drugs are largely unnecessary beyond that. Therefore, in my mind, any drug should have a dramatic benefit and a minimal long-term risk at an acceptable cost. After all, are you interested in lowering your heart attack risk for two-years? Or are you interested in lowering your risk over your lifetime?

 

Don’t get me wrong. There may still be a very limited role for PCSK9 inhibitors.

 

For very high-risk patients in whom you have tried everything (especially intensive lifestyle modifications) yet they are still likely to have another heart attack in the near future, then PCSK9 inhibitors could be a good option to reduce their heart attack risk by 0.6% per year, even though it won’t affect their risk of dying.

 

Beyond that, however, they have no proven benefit and no clear role in medical therapy. They are very expensive, and they are likely going to show significant long-term adverse effects when used for more than 2-years. Tread lightly with PCSK9 inhibitors. 

 

Action item:

When you read the headlines, and hear the news about the incredible benefits of PCSK9 inhibitors, please remember to put it all into context. Use this article as a guide to clarify where the trial has merits and where there are still unanswered questions. As always, if you have any questions, please do not hesitate to contact us at info@DrBretScher.com.

 

Thanks for reading.

 

Bret Scher, MD FACC

Cardiologist, author, founder of Boundless Health

www.DrBretScher.com

 

 

 

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