In addition to enhancing cognition …

Galantamine
Cuts Mortality

In a long-term study, the death rate was significantly lower
for those taking galantamine versus those taking placebo

By Will Block

B y a slight stretch of imagination, new research suggests that mind triumphs over matter. At least it signifies that life is a hierarchy in which it is not possible to have a healthy body without a healthy mind. A new study strongly indicates that galantamine—well known to readers of this publication—might not only be beneficial for the mind but for the body as well, and that they are inextricably inter­related.

Last December in Hollywood, Florida, exciting new findings were presented at the American College of Neuropsychopharmacology 51st Annual Meeting (ACN 51) by a group of investigators reporting on a large long-term study. This multicenter study showed a remarkable difference in the death rate among a large group of patients suffering from mild to moderately severe Alzheimer’s disease who were given either galantamine or placebo. There was a significantly lower mortality rate in patients who were treated with galantamine—an herbal medicine extracted from a natural source and also a synthesized drug—compared to placebo.


There was a significantly
lower mortality rate in patients who
were treated with galantamine
compared to placebo


An Ethical Trial Termination

In fact, the difference was so great that before the trial was completed, at the beginning of the study’s final interim mortality analysis, an independent Data Safety Monitoring Board (DSMB) recommended that the study be terminated early due to the dramatic difference in the numbers of deaths between the two groups. They reasoned that because it was so clear that galantamine was saving lives, it was unethical to continue the study and continue giving the placebo, when galantamine was so much more beneficial. Galantamine appeared to prevent death!

Figure 1. The Alzheimer’s patients taking galantamine had 70% fewer deaths than Alzheimer’s patients taking placebo.
LEM1304fig1_272.gif
(click on thumbnail for full sized image)

Following the termination, when the data were unblinded, it was apparent that mortality was significantly lower in patients treated with galantamine, compared to patients who received placebo. The death rate was 3.1 percent for galantamine versus 4.9 percent for placebo. When the final analysis was calculated, there were 89 deaths altogether, with 33 (3.2 percent) in the galantamine group and 56 (5.5 percent) in the placebo group. This was a 70% difference! (See Fig.1.)

This was a large multicenter (conducted at 127 sites in 13 countries) double-blind placebo-controlled study involving 2051 patients who were randomized, of whom 1,023 were in the placebo group and 1,028 were in the galantamine group. The mean age was 73 years in both groups (ranging between the ages of 45 and 92), and most patients were women (65%) and white (99.9%). Eventually, 339 patients treated with galantamine and 322 given placebo completed the two-year study. There were no notable demographic differences between groups. Due to the early termination of the study, the mean duration of treatment was approximately 16 months.


Galantamine was saving lives.


About two-thirds of the patients had been treated with the maximum dose of 24 mg galantamine; only 3.4% received less than the targeted 16 mg. Thus the patients were treated with 16–24 mg of galantamine or with placebo daily.

The Life-Saving Power of Galantamine

These findings from work conducted at the Center for Medicine of the Elderly in Niedersachsen, Germany were made available from a press release from the sponsoring group1 and an abstract of the study2 published by nature.com, a scientifically respectable website, which hosts many first-rate publications. Normally, we would not comment on such a presentation because the paper has not yet been checked for validity and finished for publication. But for the same reason that the DSMB made their decision to terminate the trial, we have decided to publish the findings as they have been presented. The difference in the apparent ability of galantamine to reduce death among early to mid-stage Alzheimer’s was highly significant and our readers need to be notified of this finding. Although it is not clear from the presentation, it may also be that these results could pertain to mild cognitive impairment (MCI) as well as Alzheimer’s disease! MCI may represent a prodromal (possessing early symptoms) stage of dementia and confer a high risk for conversion (perhaps 10–15%) to Alzheimer’s disease.3

Galantamine Helps Maintain Thinking as It Preserves Life

Significantly, according to the research presented at ACN 51, subjects treated with galantamine also had much lower declines in cognitive impairment after two years, compared to those in the placebo group.

When the study began, the baseline for the subjects as determined by the Mini Mental Status Evaluation (MMSE), a validated measure of cognition, was 19. This commonly used test is a brief 30-point questionnaire, which can, in about 10 minutes, sample functions including arithmetic, memory and orientation. The primary efficacy endpoint was the change in the MMSE score from baseline until month 24.


An independent Data Safety
Monitoring Board recommended
early termination of the study
owing to an imbalance of deaths
between the two groups.


A secondary efficacy endpoint was the change in the daily activities—as measured by the Disability Assessment in Dementia (DAD) scale—from baseline to the months 12 and 24. The primary safety endpoint was mortality. The primary safety endpoint was the rate of mortality or death over two years. The secondary safety endpoint was the incidence of Treatment Emergent Adverse Event (TEAE), including serious adverse events, over two years.

Figure 2. Mini Mental Status Evaluation (MMSE) scores. Higher scores represent better cognition.
LEM1304fig2_272.gif
(click on thumbnail for full sized image)
After 24 months, the mean MMSE scores deteriorated from a baseline of 19 to 16.9 and 17.5 for the placebo and galantamine groups, respectively. (See Fig. 2.) Furthermore, there was a significantly greater decline from baseline in MMSE at month 6 in the placebo group compared with the galantamine group.

An important benchmark of sinking into Alzheimer’s disease is a reduction in the change in activities of daily living (i.e., the ability to take care of oneself). For the placebo group, these results were significantly worse than for the galantamine group.

Few Adverse Events

Fifty percent of the placebo group and 54 percent of the galantamine group reported at least one TEAE. But only approximately 12 percent of patients reported serious adverse events in both groups. Those treated with galantamine reported numerically more TEAEs. However, they were mild and mostly gastrointestinal disorders, such as nausea or vomiting. Moreover, the incidence and types of serious TEAEs were similar in both groups, except for mortality, which was significantly higher in the group of patients that received placebo.


There was a significantly
greater decline from baseline in
MMSE at month 6 in the
placebo group compared with
the galantamine group.


Efficacy Endpoint of the Study

The primary efficacy endpoint was the change from baseline in the MMSE score at month 24. Secondary efficacy endpoints included cognitive change from baseline to month 6 as measured by the MMSE, and change in function from baseline to month 24 as measured by the DAD.

The galantamine group initially received 8 mg of drug daily, and the dose was increased to 16–24 mg daily during the first 12 weeks of the study. Thereafter, patients were maintained on 16–24 mg of galantamine daily.

What is Known About Alzheimer’s Disease

Alzheimer’s disease, the most common form of dementia, is a degenerative brain disease that is not typical of what is referred to as “normal aging” by the conventional medical community. The horror of this disease is that it gradually destroys a person’s cognitive and functional abilities, like a silent thief operating in the night. These dysfunctions include memory degeneration, loss of consciousness, and the loss of one’s personality and the ability to perform the common activities of everyday life such as bathing and eating.

Alzheimer’s disease is estimated to affect more than five million people in the United States, and is the sixth leading cause of death here. Worldwide, together with other dementias, Alzheimer’s is estimated to affect 35.6 million people, as of 2010. What’s worse, the number of affected individuals is projected to increase every 20 years by a factor of nearly two, increasing to 65.7 million in 2030 and 115.4 million by 2050. The costs of all dementia are estimated to be around one percent of global gross domestic product (GDP) in 2010 with US costs reaching $600 billion, including informal unpaid care, combined with community or residential-based care and treatment.

The Promise of Galantamine

Galantamine is an acetylcholinesterase inhibitor approved to treat symptoms of mild to moderate Alzheimer’s disease. While there is no evidence that galantamine alters the course of the essential process of dementia, there is evidence that when combined with a choline donor, it may slow the process and possibly (especially when combined with choline donors and other brain nutrients) reverse it (see “Alzheimer’s Breakthrough” in the April 2012 issue). Also, as this study shows, galantamine also appears to reduce mortality. Exactly what is galantamine’s mechanism is unknown. However, it is believed to achieve part of its therapeutic effect by increasing the concentration of the neurotransmitter acetylcholine by inhibiting the cholinesterase enzyme, which breaks down acetylcholine.


The galantamine group
initially received 8 mg of drug daily,
and the dose was increased to
16–24 mg daily during the first
12 weeks of the study.
Thereafter, patients were maintained
on 16–24 mg of galantamine daily.


Also, while the cause of cognitive impairment in Alzheimer’s disease is not fully comprehended, it is thought that the premature breakdown of the neurotransmitter acetylcholine causes the degeneration of neurons in the brains of those with Alzheimer’s. The greater the loss of these neurons, the greater the degree of cognitive impairment. More precisely, galantamine prevents this breakdown by inhibiting the enzyme acetylcholinesterase. It also enhances the function of nicotinic receptors in the cholinergic system (a system activated by or capable of liberating acetylcholine). Additionally, the pathological hallmark of Alzheimer’s disease is the growth of amyloid plaques, which also accompanies the neuronal deterioration.


This study shows, again,
that the reduction of cognitive
performance and activities of daily
living can be slowed by galantamine.


In the prescription world, galantamine is approved for treatment of mild to moderately severe dementia of the Alzheimer type (in some countries outside of the US, galantamine is also indicated for Alzheimer’s dementia with cerebrovascular disease). The efficacy of galantamine in the treatment of mild to moderately severe dementia of the Alzheimer type has been demonstrated in several Phase 3, double-blind, placebo-controlled studies lasting up to 6 months, and occasionally longer. This current study was conducted to assess the risk-benefit profile following 2 years of galantamine dosing in patients with Alzheimer’s.


The study also provides evidence for
the first time that galantamine can
reduce the mortality of the disease.


This 2-year study is the longest placebo-controlled study of galantamine in patients with mild to moderately severe Alzheimer’s disease conducted to date. In this study, galantamine was associated with a significantly lower mortality rate and a significantly slower decline in cognition and activities of daily living.

First Study to Show Longevity Effect

This is the first study with an acetylcholinesterase inhibitor, which not only shows once again that the reduction of cognitive performance and activities of daily living can be slowed by these substances, but also for the first time provides evidence that the treatment can reduce the mortality of the disease. Whether the results can be generalized to other acetylcholinesterase inhibitors is unclear.


The thinking of the alkaloid
researchers in Europe, who sold the
use patent to the pharmaceutical
company that now markets the
synthetic galantamine, is that the
flower extracted form is far superior.


The galantamine used in this study was a synthetic drug, but initially plant derived. The original galantamine was extracted from the species of bulbous herbaceous plants in the family Amaryllidaceae, subfamily Amaryllidoideae. Included in this family are snowdrops, daffodils, spider lilies, and a few others. It takes huge amounts of these flowers to get a little galantamine, so it cannot be made inexpensively. The thinking of the alkaloid researchers in Europe, who sold the use patent to the pharmaceutical company that now markets the synthetic galantamine, is that the flower extracted form is far superior. Extracted from snowdrops, that form is available as a nutritional supplement in the United States, and has been available for more than 12 years, before it was offered as a drug.

References

  1. www.janssenrnd.com/media-center/newsroom/press-releases
  2. Hager K, Baseman AS, Han JH, Sano M, Richards HM. In a 2-Year Placebo-controlled Randomized Trial, Galantamine-treated Patients had Lower Mortality Rates and Slower Decline in Cognition and Activities of Daily Living. Neuropsychopharmacology. (2012) 38, S328. doi:10.1038/npp.2012.221 www.nature.com/npp/journal/v38/n1s/full/npp2012221a.html . Updated: December 5, 2012. Accessed: February 9, 2013.
  3. Defrancesco M, Marksteiner J, Deisenhammer E, Kemmler G, Djurdjevic T, Schocke M. Impact of White Matter Lesions and Cognitive Deficits on Conversion from Mild Cognitive Impairment to Alzheimer's Disease. J Alzheimers Dis. 2012 Dec 19. [Epub ahead of print]


Will Block is the publisher and editorial director of Life Enhancement magazine.

Featured Product

  • Learn more about Galantamine benefits and implementation strategies.

Ingredients in this Article

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator