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Mainstream Doctors Still Confused About Homocysteine

June 2006

By William Faloon

Two months ago, the New England Journal of Medicine published two studies showing that moderately lowering homocysteine blood levels did not reduce heart attack risk in those with existing cardiac or vascular disease.

The following statement was made in an editorial that accompanied these two articles:

“. . . the results lead to the unequivocal conclusion that there is no clinical benefit to the use of folic acid and vitamin B12 (with or without vitamin B6) in patients with established vascular disease.”1

The media then boldly proclaimed:

“Hope Abandoned for Benefit to Lowering Homocysteine” Contrary to these negative opinions, the two studies in the New England Journal of Medicine confirm what Life Extension long ago published about vascular disease and what steps are required to achieve optimal homocysteine control.

As a reader of Life Extension magazine, you have a front row seat to a raging debate that could very well affect how many Americans will develop heart disease, stroke, osteoporosis, Alzheimer’s disease, blindness, depression, and other disorders associated with excess homocysteine.

Homocysteine was first theorized to cause vascular disease when autopsy results of young people revealed atherosclerotic plaque in those with very high homocysteine levels. Over a 37-year period, doctors uncovered startling evidence linking elevated homocysteine to increased risks of heart attack,2-36 stroke,37-50 and other disorders in aging adults.

In addition to human epidemiological data, scientists have identified specific mechanisms by which homocysteine causes the most common age-related diseases. One of the New England Journal of Medicine authors summed up these toxic mechanisms by stating:

“ . . . homocysteine is an atherogenic determinate that promotes oxidant stress, inflammation, thrombosis, endothelial dysfunction, and cell proliferation.”1

Based on the description above, excess homocysteine would appear to be linked to virtually every human degenerative disease. If this is the case, then why did the same author state that reducing homocysteine had no effect in preventing heart attack?

Homocysteine May Not Have Been Reduced Enough

Scientific studies dating back to the early 1990s indicate that optimal homocysteine levels should not exceed 9-10 micromoles per liter (µmol/L),51 and ideally should be even lower than that, perhaps under 7 µmol/L for optimal risk reduction.52

One epidemiological study demonstrated that homocysteine levels above 10 µmol/L are associated with an increase in heart attack risk.22 Another study showed that homocysteine levels as low as 9 carry long-term danger, with cardiac risk escalating more sharply when homocysteine levels are at 15 or greater.17 Still another (Japanese) study showed that those with a homocysteine level below 7 were much less likely to suffer a stroke than patients with homocysteine levels higher than 11.51

The New England Journal of Medicine recently published two studies showing no benefit to lowering homocysteine in those with pre-existing vascular disease. In the first study, baseline homocysteine levels of 12.2 µmol/L were reduced to a mean of 9.7 over a two-year period. Study participants in the active group were given one daily supplement that consisted of 2.5 mg of folic acid, 1 mg of vitamin B12, and 50 mg of vitamin B6.53

In the second New England Journal of Medicine study, the baseline homocysteine level of 13 µmol/L was reduced to a mean of 9.6 after three years. One active group in this study received only 40 mg of vitamin B6, while other groups received 0.8 mg of folic acid and 0.4 mg of B12 with and without 40 mg of B6.54

Life Extension long ago advocated that members take aggressive steps to keep homocysteine levels below 7-8 µmol/L.55-57 The rationale was based on an extrapolation of the existing published studies relating to homocysteine blood levels and heart attack risk.

Blood Level
Risk of Dying
(3.9-5.3 years)

Less than 9 µmo/L


Between 9 and 15


Greater than 15


For instance, an earlier study17 in the New England Journal of Medicine looked at mortality in coronary artery disease patients and found the following: As the table above shows, homocysteine blood levels between 9 and 15 µmol/L doubled mortality rates compared to values less than 9, while homocysteine above 15 increased mortality by an astounding 6.47 times compared to levels below 9!

The two recent studies published in the New England Journal of Medicine failed to reduce homocysteine to the levels that the Life Extension Foundation long ago stated were needed to reduce heart attack risk. In fact, these two recent studies failed to reduce homocysteine to the less than 9 µmol/L level that had previously been shown in the same medical journal to confer benefit.

The question still begs, however, as to why moderate homocysteine reduction did not result in at least some reduction in heart attack risk. The answers become obvious as the study’s design methods are uncovered.

Unhealthy Study Subjects

To participate in the first study that used modest doses of nutrients to moderately reduce homocysteine levels, one had to have “a history of vascular disease (coronary, cerebrovascular, or peripheral vascular) or diabetes and additional risk factors for atherosclerosis.”

To qualify for the second study that used lower potencies of nutrients, participants had to first suffer “an acute myocardial infarction,” more commonly known as a heart attack, within seven days of enrollment in the study.

Based on the enrollment criteria, the study subjects had to have significant pre-existing vascular impairment in order to participate. In this article, you will read why the use of these unhealthy subjects virtually guaranteed that this study would fail. Next, however, we need to emphasize that. . .

Homocysteine Level and Coronary Artery Disease Risk


Logistic regression is a statistical tool used to understand data. In the chart above, logistic regression assumes that an increase anywhere along the curve for homocysteine values will have the same effect, regardless of baseline value. Using an additive model for logistic regression, the risk of cardiovascular disease is greater with homocysteine values at the upper end of the "normal" range compared to values at the lower end of the “normal” range. This risk (comparing the upper end of the “normal” range such as 13-15 µmol/L vs. the lower end of the “normal” range such as 7-8 µmol/L) is 4 to 5 times greater.

The Study Period Was Too Short!

Based on the enrollment criteria, the study subjects had already suffered significant arterial damage over most of their lifetime. The study design expectation was that within two or three years, taking modest doses of only three nutrients would somehow protect the test subjects against future vascular events.

Please note the word “within” when describing the study period. While the first study lasted two years and the second study lasted a little over three years, any participant who encountered a vascular event even one day after the study’s commencement was considered a statistic.

In other words, if a study participant suffered any kind of vascular disease after they took even one dose of B vitamins, then that person was listed as a “failure,” meaning that he or she filled a statistical column showing no benefit to B vitamins as far as this study was concerned.

Remember that these were high-risk participants with pre-existing vascular disease. It is absurd to expect that moderately lowering homocysteine within a very short time period would result in a miraculous disease reduction in these unhealthy individuals.

As any enlightened person knows, atherosclerosis does not develop overnight. Initial arterial lesions are sometimes seen in teenagers. The process of inner arterial wall degradation leading to atherosclerosis lasts for many decades. When one has pre-existing vascular disease—as was the case for most of these study subjects—the arteries are severely damaged and the risk of future arterial-related diseases is high.

For people with pre-existing arterial disease, protecting against a future heart attack or stroke requires extraordinary effort. Swallowing one modest-dose daily supplement after you have developed significant vascular disease is not going to do it!

Baseline Homocysteine Levels May Not Have Been High Enough

We discussed before that the two studies failed to adequately reduce homocysteine levels to optimal safe ranges. While that is one significant flaw, another defect in these two studies was that the subjects’ homocysteine levels were not particularly high to begin with.

To clarify this point, while some studies show that homocysteine levels above 7-9 µmol/L increase vascular disease risk, the most lethal effect occurs when levels exceed 13-15. The subjects chosen for these two studies had baseline homocysteine levels of 12.2 and 13 on average, which were reduced to 9.7 and 9.6, respectively. Existing data indicate that there may not have been much of a statistical difference between the study subjects’ baseline levels and their homo-cysteine levels two and three years later.

The following chart using data from a study published by the American Heart Association helps explain why the baseline homocysteine levels in these two studies may not have been high enough.58

As one can see, cardiac risk increases incrementally with rising homocysteine. Generally speaking, when the odds ratio exceeds 2.0 or 2.5 in epidemiology studies, scientists become concerned that risk increases. In this chart, a homocysteine level of about 13 µmo/L corresponds to an odds ratio of about 2.0 to 2.5. From the chart, the risk associated with a homocysteine level of 13-15 is 4 to 5 times greater compared to the risk associated with a homocysteine level of 7-8.It should be noted that this chart uses logistic regression to describe heart attack risk in relationship to increasing homocysteine levels.

Homocysteine May Cause More Strokes than Heart Disease

Homocysteine Level

Stroke (Ischemic) Risk

Less than 7 µmol/L

Comparison group

Between 7 and 9

26% increased risk (relative to the comparison group)

Between 9 and 11

31% increased risk (relative to the comparison group)

Above 11

74% increased risk (relative to the comparison group)

Heart disease remains the number-one killer in the Western world, but the leading cause of disability is stroke.59,60 The paralyzing effects of stroke are often far more feared than a heart attack, and stroke is the third leading cause of death in the United States.61

Studies examining stroke incidence indicate that elevated homocysteine is a greater risk factor for stroke than it is for cardiac disease. In other words, even a modest increase in homocysteine is more likely to damage one’s brain than one’s heart.

The following table is based on data from the stroke study mentioned earlier51 and helps elucidate these startling findings.

As the table above clearly shows, while homocysteine levels below 7 µmol/L are ideal, a sharp increase in stroke incidence occurs when homocysteine levels exceed 11.51 This study helps corroborate Life Extension’s longstanding position that optimal homocysteine levels should be under 7-8 µmol/L.62-64