Niacin is/was/will always be the Good One - Penberthy

Laropiprant is the Bad One; Niacin is/was/will always be the Good One

by W. Todd Penberthy, PhD

(OMNS July 25, 2014) Niacin has been used for over 60 years in tens of thousands of patients with tremendously favorable therapeutic benefit (Carlson 2005). In the first-person NY Times best seller, "8 Weeks to a Cure for Cholesterol," the author describes his journey from being a walking heart attack time bomb to a becoming a healthy individual. He hails high-dose niacin as the one treatment that did more to correct his poor lipid profile than any other (Kowalski 2001). Many clinical studies have shown that high doses of niacin (3,000-5,000 mg plain old immediate release niacin taken in divided doses spread out over the course of a day) cause dramatic reductions in total mortality in patients that experienced previous strokes (Creider 2012). High dose niacin has also been clinically proven to provide positive transformational relief to many schizophrenics in studies involving administration of immediate release niacin in multi-thousand-milligram quantities to greater than 10,000 patients (Hoffer 1964; Osmond 1962). Most importantly, after 60 years of use the safety profile for niacin (especially immediate release niacin) remains far safer than the safest drug (Guyton 2007).

Bad Reporting

So why has the media suddenly presented the following niacin alarmist headlines in response to the most recent study in the New England Journal of Medicine?

"Niacin drug causes serious side effects, study says" - Boston Globe, 7/16/14

"Niacin safety, effectiveness questioned in new heart study" - Healthday News, 7/17/14

"Doctors say cholesterol drug risky to take" - Times Daily, 7/16/14

"Niacin risks may present health risks claim scientists" - Viral Global News, 7/17/14

"Studies reveal new niacin risks" - Drug Discovery and Development, 7/17/14

"No love for niacin" - Medpage Today, 7/17/14

"Niacin could be more harmful than helpful" - Telemanagement, 7/18/14

The truth of the matter is that the study quoted and used laropiprant (trade names: Cordaptive and Tredaptive). Laropiprant is a questionable drug and the results say next to nothing about niacin. The study compared over 25,000 patients treated with either niacin along with laropiprant, or placebo. The patients in this study had previous history of myocardial infarction, cerebrovascular disease, peripheral arterial disease, or diabetes mellitus with evidence of symptomatic coronary disease. The side effects observed in those who took the laropiprant-niacin combination were serious and included an increase in total mortality as well as significant increases in the risk for developing diabetes.

For responsible reporters, this should have raised the question of which compound, the drug laropiprant, or the vitamin niacin, is the culprit.

Such side effects have not been seen in over 10 major clinical trials of niacin involving tens of thousands of patients, not in over 60 years of regular usage of niacin in clinics across the country. However, niacin causes a warm flush on the skin. Some people find the warm niacin flush uncomfortable, although many people enjoy this temporary sensation. In this study, niacin was given in combination with laropiprant, a drug that prevents the niacin flush. By including a dose of laropiprant along with the niacin to eliminate the flush, the thought was that more patients could benefit from niacin without complaint. But in fact the niacin flush is healthy. A reduced flush response to niacin is a diagnostic for increased incidence of schizophrenia, and this assay is now widely available (Horrobin 1980; Messamore, 2003; Liu 2007; Smesny, 2007).

Problems with Laropiprant

So what about the other half of the combo, the drug laropiprant?

• Laropiprant has never been approved by the FDA for use in the USA and when taken alone has been shown to increase gastrointestinal bleeding. *
• Laropiprant interferes with a basic prostaglandin receptor pathway that is important for good health.
• Last year Merck announced it would withdraw laropiprant worldwide due to complaints from continental Europe. Therefore the clinical trials in this most recent study could only be performed in the UK, Scandinavia, and China.

So why did so many media outlets and even some MDs conclude that niacin was the problem? Simple: none of the headlines mentioned laropiprant, which is quite clearly the real culprit that caused the side effects reported. The simplest way to put it is to say that sensational stories promulgated by the media are quite often completely wrong. This suggests a hidden agenda.

Confusing and fantastical headlines can increase readership for hysteria-based business models. Which headline is likely to garner the greatest attention: "Laropiprant is a Dangerous Medication that has Not Been Approved by the FDA" or "Niacin Causes Serious Side Effects"? The correct headline would be, "Niacin doesn't cause serious side effects; drugs do."

Why the B Vitamins Are So Important

The B vitamins were discovered due to terrible nutritional epidemics: pellagra (niacin/vitamin B3 deficiency) and beriberi (thiamine/vitamin B1 deficiency). We are very sensitive to a deficiency of niacin. Over 100,000 people died in the American south in the first two decades of the 20th century due to a lack of niacin in their diet. It was perhaps the worst nutritional epidemic ever observed in modern times, and was a ghastly testimony to how vulnerable the human animal is to niacin deficiency. The pellagra and beriberi epidemics took off shortly after the introduction of processed foods such as white rice and white flour. Poor diets, mental and physical stresses, and certain disease conditions have all been proven to actively deplete nicotinamide adenine dinucleotide (NAD) levels, causing patients to respond favorably to greater than average niacin dosing.

How is it possible that niacin can be useful for many different conditions? It seems too good to be true. The reason is that niacin is necessary for more biochemical reactions than any other vitamin-derived molecule: over 450 different gene-encoded enzymatic reactions (UniproKB database of the Swiss Institute of Bioinformatics; (Penberthy 2013)). That is more reactions than any other vitamin-derived co-factor! Niacin is involved in just about every major biochemical pathway. Some individuals, who have a genetically encoded amino acid polymorphism within the NAD binding domain of an enzyme protein, will have a lower binding affinity for NAD that can only be treated by administering higher amounts of niacin to make the amount of NAD required for normal health. Genetic differences such as these are why many individuals require higher amounts of niacin in order for their enzymes to function correctly (Ames 2002).

It is a deadly shame that the media so often ignores this information. Fortunately, many physicians will see through the recent headlines that give misinformation about niacin, having already personally witnessed how effective high dose niacin therapy is for preventing cardiovascular disease.

Nutrients are the Solution, Not the Problem

So what is the solution? At the end of the day the data on patients with problem cholesterol/LDL levels still support 3,000-5,000 milligrams of immediate-release niacin as the best clinically-proven approach to maintaining a healthy lipid profile. Niacin in 250mg to 1000mg doses can be purchased inexpensively from many sources. Extended-release niacin is the form of niacin that is most frequently sold by prescription, but it has more side effects than immediate release (plain old) niacin. . . and it costs much more.

Tangential to niacin but pointed to cardiovascular disease, conventional medicine is finally beginning to respect chelation therapy as an approach owing to the recent unparalleled positive clinical results for cardiovascular disease patients with diabetes - up to 50% prevention of recurrent heart attacks and 43% reduction in death rate from all causes (Avila 2014). Some times chelation therapy can be expensive. However, there are other inexpensive approaches include high dose IP6 therapy that are yet to be conventionally appreciated. Other supplements desirable for any ideal cardiovascular disease: a nutritional regimen include additional vitamin C, magnesium, coenzyme Q, fat soluble vitamins (A, D, E, and K2), and grass-fed organic butter. Your ideal intake varies with your individuality.

Nutrients such as niacin you need. Media misinformation you don't.

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Read the complete article here.

Putting "Relative Risk" in perspective - Eades

Absolute risk versus relative risk: Why you need to know the difference

30. December 2013,

Six years ago, the airwaves were alive with Lipitor ads. Lipitor, a statin and the largest selling drug in the world at that time, was being challenged by other less expensive statins that had gone off patent, so Pfizer, the manufacturer, was blanketing the media in an effort to keep sales humming.

Pfizer had a series of ads featuring Dr. Robert Jarvik, one of the developers of the first artificial heart. These ads were a first in that a real doctor had never appeared in an ad touting a drug. As I posted at the time, Pfizer and Dr. Jarvik got into some trouble because they all played a little fast and loose with the truth about Dr. Jarvik’s credentials.



Aside from the misrepresentation by both Pfizer and Jarvik, one of the claims many of these ads made was that by taking Lipitor you could reduce your risk of heart disease by 36 percent. Sounds pretty good. I would like to reduce my risk of heart disease by 36 percent as did millions of people who went on the drug.

These ads weren’t technically misleading, but they didn’t tell the whole truth, because the 36 percent reduction in heart attack risk was what’s called a relative risk reduction.

Relative Risk
Relative risk is always stated as a percentage. Let’s say we do a study in which we randomize 200 subjects in two groups of 100. One group (the study group) takes a drug, and the other (the control group) takes a sugar pill. We keep the subjects in the two groups on their pill regimen and wait for, say, ten years to see what happens. After ten years, we find that 90 people in the group taking the sugar pill died while only 60 people taking the drug died.

We can then do the following calculation. 90 − 60 = 30. 30 divided by 90 = 0.33. Converting 0.33 to a percentage = 33 percent. Which is the relative risk. If this were an actual study, you could say people taking the drug reduced their risk of dying by 33 percent.

Would this be important? Absolutely. In this case as least. Why? Because 150 people out of 200 died. This means most of the people in the study died, so a 33 percent reduction in risk is huge. I would be all over this drug in a heartbeat.

So what’s the problem, then, with the 36 percent reduction in risk found in the Lipitor study? And why shouldn’t people be begging to go on Lipitor?

Because they need to know the absolute risk before the relative risk becomes important.

Absolute Risk
The absolute risk is simply the total risk for whatever is being studied. In our made up example above, the study end point we were looking for was death. In that example, 150 out of 200 died. So if you were a subject in that study, your absolute risk of dying would be 150 divided by 200 or 75 percent, which is very high.

If your absolute risk of crashing during a commercial airline flight were 75 percent, you would never fly. But if you absolutely had to fly, and one airline offered a 33 percent reduction in risk of crashing (relative risk), you would be stupid not to fly that airline.

To make sense out of relative risk, you’ve got to know the absolute risk.

Let’s go back to our Lipitor claim.

The 36 percent relative risk reduction figure came from a study published in Drugs titled Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.

This study was a subset of a larger study in which about 20,000 subjects with high blood pressure and three other cardiovascular risk factors were randomized into two groups, the subjects in each of which got one of two blood pressure lowering medications. From this larger group, a little over 10,000 subjects were found who had cholesterol levels at or below 250 mg/dl (6.5 mmol/l). In addition to the blood pressure medications, half of this group got 10 mg of Lipitor (atorvastatin) per day while the other half got a placebo along with their blood pressure medication.

In the Lipitor/placebo arm of this study, the endpoint was defined as a non-fatal heart attack or death from heart disease.

After about 3.3 years, this arm of the study was discontinued because there were a significant number of either heart attacks of deaths from heart disease in the placebo group, and the researchers felt it was unethical to continue the study.

When the data were examined, it turned out that the group taking Lipitor experienced a 36 percent decrease in relative risk for heart disease. Thus the barrage of ads for Lipitor that followed.
Even websites aimed at doctors, using info from the Lipitor package insert, showed graphics designed to make any doctor grab for the Lipitor pre-printed prescription pad. This graph is 100 percent accurate, but, as we shall see, hugely misleading.


Figure 1 below is a graphic showing what that 36 percent relative risk looks like.

Figure 1. Relative risk of 36 percent with a large absolute risk.

 

Pretty impressive, isn’t it? Makes you wonder why anyone wouldn’t want to take Lipitor. Problem is, Figure 1, which I made up, shows a relative risk differential of 36 percent, but it also shows a large absolute risk.

Looking at Figure 2 below, which shows the actual absolute risk of experiencing a heart attack or dying from heart disease in this study, you can see that the 36 percent relative risk reduction is accurate. But does it really make you want to stampede to the pharmacy to pick up your Lipitor? Remember, these subjects all had high blood pressure and two other risk factors for heart disease, yet their absolute risk is pretty low. Would you want to take a medicine that could give you muscle aches and pains along with muscle wasting, short term memory loss and possibly fatal liver or kidney damage based on the absolute risk shown in Figure 2?

Figure 2.  Relative risk of 36 percent with actual absolute risk in the Lipitor study. 

 

If you compare Figure 1 to Figure 2 above, both of which have the same relative risk, you can readily see that the absolute risk is extremely important. If the absolute risk is high, as it is in Figure 1 at the top, then the relative risk becomes important.

If, as in Figure 2, the real Lipitor vs placebo graphic, the absolute risk is small, then not so much so. Both Figure 1 and Figure 2 show the same relative risk, but not anywhere close to the same absolute risk. Which is why you always want to know the absolute risk before you make a decision on anything based on relative risk. Because absolute risk is usually pretty low in drug studies, the pharmaceutical industry typically uses the relative risk number to sell their medicines.

In the case of statins, most people go on statins because what they really fear is dropping dead of a heart attack, and they feel the statins are protective.

What happened in this study? There were two more deaths in the placebo group than in the Lipitor group, but that number wasn’t statistically significant. Figure 3 below is a graphic showing the absolute risk of having a fatal heart attack in the Lipitor trial.

Figure 3. Relative and absolute risk of fatal heart attack in the Lipitor study.

 

Not a huge absolute risk.

Let’s look at another example that is much more dramatic than the Lipitor study above.

I pulled a paper from the New England Journal of Medicine (NEJM) looking at coronary artery calcification (CAC) scores and risk for having a heart attack.

Approximately 20 percent of the plaque in coronary arteries is composed of calcium, which shows up on X-rays. But since the heart is constantly in motion, it’s difficult to see the calcium in standard X-rays of the chest. Specialized CT machines, however, can take extremely fast photos of the heart and actually see the calcium in the coronary arteries. A computer program then converts this calcium into a score, which is simply a number. If you have a zero score, you have no calcium accumulation, which means you probably don’t have any plaque to speak of. You could have some soft plaque that hasn’t yet calcified, but a zero CAC score is definitely a good one.

The NEJM study looked at CAC scores of 6,722 subjects and broke them out into one of four groups. Zero, CAC score of 1-100, CAC score of 101-300, and CAC score of greater than 300. These groups were followed for about 4 years on average for the main endpoint of the study, which was a major coronary event, defined as a heart attack or death from coronary heart disease.

You can see the relative and absolute risk in the graphics below. Upper left is zero CAC score. Upper right, 1-100 CAC score. The lower left is 101-300 CAC score, and the lower right is greater than a 300 CAC score.

Figure 4. Relative and absolute risks for various CAC scores.  Zero upper left. 1-100 CAC upper right.

101-300 CAC lower left.  Greater than 300 lower right.

 

As you can see, the risk for a major coronary event is negligible with a CAC score of zero. And the risk increases as the CAC scores go up. The subjects in this study who had CAC scores above 300 experienced 19 times more major coronary events than did those with zero CAC scores. Which would mean a 300+ CAC score carries a relative risk of 1900 percent* as compared to a zero, which is humongous. But looking at the absolute risk tells a different story.

I’ve seen patients with 300+ CAC scores come unglued. Granted, it’s not a score you want to see, but it doesn’t mean you’re going to die the next day. A lot of people feel that way, though. Which is why knowing the absolute risk is important before you decompensate over a high relative risk for this or any condition.

If you would like to play around with these absolute and relative risk graphics, you can do so at this site.  Keep the site bookmarked, so the next time you come across a relative risk, look up the actual risk and graph it.  Only then will you know the true risk involved.

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*I used a relative risk score based on the raw data from the study.  If you look at the actual study (linked above), you see different relative risks than what I have.  The ones in the study are lower because the authors extrapolate the data out longer and take into account when the events happened.  So, if you happen to have a high CAC score, your risk is lower than what I show above, which was strictly for illustrative purposes.
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Read the complete article here.

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20140721 Added this link to good video on relative risk. Well worth the watch.

Effect Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction - JAMA

Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction:  The TACT Randomized Trial                 

ABSTRACT 

 

 

Importance  Chelation therapy with disodium EDTA has been used for more than 50 years to treat atherosclerosis without proof of efficacy.

Objective  To determine if an EDTA-based chelation regimen reduces cardiovascular events.

Design, Setting, and Participants  Double-blind, placebo-controlled, 2 × 2 factorial randomized trial enrolling 1708 patients aged 50 years or older who had experienced a myocardial infarction (MI) at least 6 weeks prior and had serum creatinine levels of 2.0 mg/dL or less. Participants were recruited at 134 US and Canadian sites. Enrollment began in September 2003 and follow-up took place until October 2011 (median, 55 months). Two hundred eighty-nine patients (17% of total; n=115 in the EDTA group and n=174 in the placebo group) withdrew consent during the trial.

Interventions  Patients were randomized to receive 40 infusions of a 500-mL chelation solution (3 g of disodium EDTA, 7 g of ascorbate, B vitamins, electrolytes, procaine, and heparin) (n=839) vs placebo (n=869) and an oral vitamin-mineral regimen vs an oral placebo. Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart. Fifteen percent discontinued infusions (n=38 [16%] in the chelation group and n=41 [15%] in the placebo group) because of adverse events.

Main Outcome Measures  The prespecified primary end point was a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. This report describes the intention-to-treat comparison of EDTA chelation vs placebo. To account for multiple interim analyses, the significance threshold required at the final analysis was P = .036.

Results  Qualifying previous MIs occurred a median of 4.6 years before enrollment. Median age was 65 years, 18% were female, 9% were nonwhite, and 31% were diabetic. The primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.99]; P = .035). There was no effect on total mortality (chelation: 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70-1.25]; P = .64), but the study was not powered for this comparison. The effect of EDTA chelation on the components of the primary end point other than death was of similar magnitude as its overall effect (MI: chelation, 6%; placebo, 8%; HR, 0.77 [95% CI, 0.54-1.11]; stroke: chelation, 1.2%; placebo, 1.5%; HR, 0.77 [95% CI, 0.34-1.76]; coronary revascularization: chelation, 15%; placebo, 18%; HR, 0.81 [95% CI, 0.64-1.02]; hospitalization for angina: chelation, 1.6%; placebo, 2.1%; HR, 0.72 [95% CI, 0.35-1.47]).

Sensitivity analyses examining the effect of patient dropout and treatment adherence did not alter the results.

Conclusions and Relevance  Among stable patients with a history of MI, use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures. These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI.
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Low Cholesterol Levels Associated With Increased Mortality - Again!

It's never bad to get a Second Opinion especially when it comes to cholesterol with the hype and mis-information surrounding the topic. Barry Grover helps with this article. Please read the complete article here.