Metformin: An Old Drug at the New Frontier of Medicine

This is a Precision Medicine

Don’t panic. You will be able to easily understand from this diagram how metformin works as a precision medicine!

In my last post I explained how metformin is derived from a “natural medicine” source that has been used for hundreds of years. I helped you understand that metformin is refined so that the dose is consistent and that it is proven to be effective and safe. I provided several references that prove metformin protects you more than other approaches that achieve the same blood sugar level. Metformin is a natural medicine that is much safer because it is pure. It is the safest and most effective component of the natural product.

That is just the beginning of the story. Metformin is so interesting because it is a precision medicine that first helped me understand the new frontier in medicine. The old model of cardiovascular disease management involved lowering the blood sugar level in diabetes and the blood pressure level in hypertension. We lowered risk factors to prevent catastrophic acute diseases like sudden death, heart attack, and stroke. Now that is all turned on its head. Disease begins decades before the catastrophe of sudden death or heart attack. It is simple. A disease is defined as an abnormal condition that affects the structure or function of part or all of the body, usually characterized by specific signs and symptoms. It represents a deviation from a state of health.

Under the old risk factor model, we were taught that metformin works by reducing insulin resistance in the liver to lower glucose levels. That has almost nothing to do with metformin’s superior protection of cells and organs. Metformin precisely and directly interferes with a fundamental deviation from a state of health. Let me introduce you to a key molecule in the new frontier of medicine— asymmetric dimethylarginine (ADMA).

ADMA concentrations are 29 to 120% higher in obese individuals when compared to lean, healthy people. That is a fundamental deviation from a state of health. When we eat fast and processed food that are so tasty we can’t stop eating them, we develop extra abdominal fat and obesity. Some of those foods more than double ADMA levels acutely.

Here is the reason that is so important. ADMA levels are increased in age, high blood pressure, diabetes, insulin resistance, high cholesterol, and high triglycerides. For a number of these conditions, there is evidence of a causal relationship. All these illnesses lead to arterial abnormalities that progress to cardiovascular diseases like heart attack, stroke, chronic kidney disease and heart attack. These conditions ultimately share common origins. ADMA is a root cause of all cardiovascular disease.

Now we are set up for the most important fact about metformin. Look at the picture below.

Metformin and ADMA are structurally identical on the left side of the molecule and that means that metformin blocks the effect of ADMA at the cellular membrane level. Signaling molecules like ADMA engage receptors in the cell wall. ADMA is like a baseball and the receptor is the catchers mitt. Because the left side of the molecule is the same, metformin can go in the catcher’s mitt and block the effect of ADMA. That is how many precision medicines work and that is a big part of the reason that metformin reduces diabetes complications more than would be expected by the degree of sugar lowering achieved. Glucose lowering explains only a small part of the benefit of metformin. Metformin protects every cell and organ in the body by blocking the effect of ADMA precisely. The effects of this relationship are profound. A single dose of metformin in an experimentally induced heart attack can reduce heart muscle damage by half whether the animal is diabetic or not! Lowering blood sugar does not explain that!

Believe it or not, the story about ADMA and metformin gets even more interesting. ADMA is a product of gene regulation (epigenetics) which is critical to normal fetal development. Epigenetic changes cause most chronic diseases. The fetus begins life as a fertilized egg— a single cell with no other function except to become other cells. Epigenetics is the process that controls which genes are switched on and which genes are off in a perfect symphony to produce a perfect baby. DNA in genes that are switched off is very tightly wound up. DNA in genes that are switched on is unwound so that the DNA is exposed to make proteins. ADMA is formed as part of that unwinding process. It is formed as part of gene activation. In fact, if a fetus does not have the gene that makes most ADMA, it only survives a few days.

That fact points to another major insight that I first had when studying metformin. Most chronic diseases are not due to changes in DNA or mutations. They are not genetic. They are due to changes in gene regulation. They are epigenetic. Genes that are essential for fetal and childhood development become quiet in healthy young adults. They are reactivated later in life by environmental factors like fast food and processed food that cause obesity or cigarette smoke to make us age faster, get sick sooner, and die earlier. Saying metformin lowers insulin resistance is like saying Tom Brady played football. It is true, but it does not begin to capture the whole story. If you understand how metformin works, you are beginning to understand the potential of the new frontier in medicine based on genetics, epigenetics, and molecular biology. Metformin may be the best chronic disease medicine in the box and you can get it for under $10 a month.