On January 26th, the Danish pharmaceutical company, Novo Nordisk, announced that their drug, liraglutide, which will carry the trade name Victoza, has been approved by the U.S. Food and Drug Administration (FDA) for use in the United States for the treatment of Diabetes Type II. Diabetes Type II is the increasingly common adult onset form of diabetes that is associated with obesity, high blood pressure, and high cholesterol as well as high blood sugar. This new medication acts to restore normal blood glucose levels by mimicking the effects of a natural hormone in the body known as Glucagon-like peptide-1, or GLP-1. GLP-1, which is released from the gut after ingestion of sugar and carbohydrates, acts to stimulate the release of insulin from the pancreas.
It has been found that people who suffer Diabetes Type II do not release adequate amounts of GLP-1 after they have ingested meals high in carbohydrate. Thus, they are less able to restore normal blood glucose levels after such meals. Liraglutide, which mimics the effects GLP-1, restores more normal insulin responses to meals high in carbohydrate, and has thus been found to help control blood sugar levels in people with Diabetes Type II, including those who have failed to show adequate improvement with the older generation of medications, such as metformin, glipizide, and other so-called oral hypoglycemics. Liraglutide even helped those individuals lose weight! Because Diabetes Type II is now growing at unprecedented rates in the United States and other developed countries, this new and different approach to the treatment of the illness is wonderful news. What is equally interesting, however, is the possibility that this new type of medication may also help reduce the risk of Alzheimer's Disease in sufferers of Diabetes Type II, and perhaps even those without diabetes. Liraglutide is not FDA approved for the prevention of Alzheimer's Disease and studies are preliminary. But, the science is fascinating and results are very promising.
Having Diabetes Type II has been known to at least double the risk of developing Alzheimer's Disease. This is due to a number of reasons. First, many of the health problems associated with Diabetes Type II, including obesity, high blood pressure, and high cholesterol, are themselves known to increase the risk of Alzheimer's Disease. In addition, both high blood glucose and the high levels of fat in the blood lead to disturbances in the control of the burning of fuel in the body. This lack of control leads to the production of oxygen radicals and oxidative stress, which is essentially the biological equivalent of rust. Damage to cells causes inflammation, cell death, and deficits in function that all increase the deposits of sticky amyloid protein in brain tissue, which is the hallmark of Alzheimer's Disease. Amyloid not only damages and kills neurons, but also adds to further inflammation, oxidative stress, poor energy supply, and other factors that go on to stimulate even more deposition of amyloid. Thus, the condition spirals out of control. By reducing these manifestations of Diabetes Type II, liraglutide may reduce the risk of Alzheimer's.
Liraglutide may further reduce the risk of Alzheimer's Disease through its effects on insulin. In Diabetes Type II, the difficulty in controlling blood glucose levels is not due so much to a lack of insulin, but rather to the body's failure to respond to insulin effectively. That is, in Diabetes Type II the body becomes insulin resistant. Insulin resistance has also been found to play an important role in the development of Alzheimer's Disease in people with Diabetes Type II. Insulin helps maintain the growth and vitality of neurons, has an anti-inflammatory effect in brain tissue, helps the brain rid itself of amyloid, and acts to prevent the formation of the other hallmark of Alzheimer's Disease, which is the tangles of abnormal tau protein that disrupt brain tissue and function.
Since liraglutide restores a more normal insulin response to carbohydrate intake in people with Diabetes Type II, it is possible that some of the drug's benefits are due to overcoming the body's hampered response to insulin. This alone would help control Diabetes Type II and thus reduce some risk of Alzheimer's Disease. However, there is recent evidence that liraglutide might reduce the risk of Alzheimer's by acting directly in the brain. Indeed, it has been found that the brain tissue possesses receptors for GLP-1, and thus might respond to drugs such as liraglutide.
GLP-1 has been found to stimulate the growth of neurons in brain tissue, and to prevent the death of neurons exposed to amyloid, oxidative stress, or the so-called excitotoxic effects of the neurotransmitter glutamate. Interestingly, mice engineered to lack receptors for GLP-1 in their brains, so-called GLP-1 "knock out" mice, have been shown to have deficits in learning. On the other hand, increasing the amount of natural GLP-1, by inhibiting the enzymes that destroy it, has been found to postpone the generation of lesions in the brains of mice genetically engineered to develop an Alzheimer's-like illness. Studies have now found that liraglutide itself improves the learning process of Long Term Potentiation (LTP) in mice, and that the drug also reverses some of the detrimental effects of amyloid deposition on LTP. Exendin-4, a substance that acts in much the same way as liraglutide in mimicking GLP-1, has been found to reduce brain levels of abnormal amyloid plaques in diabetic mice.
Ideally, we should avoid both Diabetes Type II and Alzheimer's Disease by proper diet, exercise, stress reduction, adequate sleep, and other healthy lifestyle choices. Indeed, many studies have shown that lifestyle changes can be more effective not only in preventing, but in reversing Diabetes Type II than are standard medications such as metformin. Moreover, we must cautious. Medical history is full of promising medications that were later found to be less than effective or even harmful. However, with the use of medications such as statins, angiotensin receptor blockers, and now liraglutide, individuals who have already developed Diabetes Type II may have a better chance for a future free of Alzheimer's Disease.
Dr. Mendelson wishes to inform the readers that he has no affiliation with or financial interest in Novo Nordisk, the pharmaceutical company that manufactures Victoza.