Off-target Effects

A study has shown that Metformin, a drug widely used in treating diabetics, is likely to reduce the risk of breast cancer. The researchers introduce the study by noting that it is now acknowledged that diabetes increases the risk of breast and other cancers—something we discussed two years ago in our book.

I’d like to remind you that “diabetes” is a diagnosis, not a biological condition. The diagnosis is something a human being does. The biological condition is a disruption to the body’s energy metabolism due to organ damage that causes blood sugar and body fat derangements and, as a consequence, results in the derangement of other organ systems, most importantly the cardiovascular and nervous systems.

In other words, the biological condition that results in a diagnosis of diabetes—“diabetes” for short—is not a chemical imbalance. It is a disruption of the normal functioning of an organ and the complex system of organs of which it is a member.

That a drug has an effect beyond its intended use should be no more surprising than the fact that the disruption to energy metabolism that causes diabetes goes well beyond blood sugar derangement—including cancer. In the pharmaceutical research literature, this distinction between the intended and unintended effect of a drug is referred to as the on-target and off-target effect respectively. “Off-target effect” is more commonly referred to as “side effect.”

The distinction between on-target and off-target effects is commercially significant, again as we discuss in our book, because researchers are actively looking systematically for those off-target effects. The reason for this work is not the hunt for damage but for other and undiscovered uses for already existing drugs. One often cited reason for this hunt is that widely used drugs such as Metformin and the statin drugs are, so to speak, known quantities regarding negative effects—“well tolerated” is a comforting phrase commonly used.

However, as I’m sure you’ve guessed or already know, the principal reason for the exploration of off-target drug effects is commercial. As widely used drugs such as Metformin and statins come to the end of their patents’ life, they can be given a new life if they can be found “safe and effective” in treating conditions other than those for which they are currently licensed by the FDA.

So the knowledge that Metformin decreases the risk of breast cancer comes from the drive by drug companies to literally sell old wine in new bottles—patented new bottles.

Before we are awestruck by the marvels of modern chemistry, I want to note that the magic made by Metformin came from the isolation of biologically active chemicals extracted from French lilac (also called goat’s rue) which was used for centuries as a traditional remedy. Romantic notions of herbalism aside, Metformin’s active ingredient works by down-regulating the enzymes that control the transcription of genes responsible for gluconeogenesis.

In English…

The body recycles lactic acid produced during muscle contraction into blood sugar, the chemical glucose—hence, gluconeogenesis, the generation of new glucose. Ordinarily, that happens when blood sugar is low—which happens while fasting, such as during sleep. When the body’s energy metabolism is deranged, it doesn’t know when to stop the gluconeogenesis process. And so blood sugars rise above normal levels. The dawn effect is a common condition for diabetics: blood sugars higher in the morning than the night before—which shouldn’t happen because you haven’t eaten anything between going to bed and getting up, unless you raid the refrigerator in your sleep, which isn’t common.

Metformin puts a stick in this wheel. It does so by disrupting the process that signals certain genes to cause the production of certain enzymes. That’s transcription.

There are alternatives. If you’re still mesmerized by magic potions—which, from a practical standpoint, is how we treat pharmaceuticals in our culture—there’s always goat’s rue. There’s another at the local liquor store. Ethanol available in distilled spirits disrupts the enzymatic process that turns lactic acid into glucose—that is, it stops the dawn effect—hence the salutary effect of a nightcap.

But what’s wrong here isn’t “natural” versus pharmaceutical magic potions. What’s wrong is magic potions as the answer to the damage done to our biology. As we all know from the stories, playing around with magic potions usually gets you in a lot of trouble.

Our biology is more than a chemical soup. Causes and cures start, not with chemicals, but with organs. Actually, they start with you. You are the one who gets diagnosed, not your beta cells or the insulin they produce. It is you who is ill. It is you who is treated.

Knowledge such as that about the effects of Metformin on breast cancer is mechanistic and partial and reductionist—both in principle and practice. Not a bad thing in itself, but quite bad when isolated from you. It treats your diabetes as nothing more than a chemical imbalance best treated with other chemicals.

That’s just wrong—especially in light of the relationship of the drug to off-target effects such as cancer risk. For over a decade, a group of researchers has advanced the idea that cancer is not a disease of cells but a disease of organs. Multi-organ illnesses such as multiple chemical sensitivity are teaching us the same lesson: what causes disease is damage to organs that ordinarily hold disease in check.

Unfortunately, methods that prevent damage to organs and repair them once damaged are more difficult to patent than magic potions that lend themselves to commercial advantage. It gives new meaning to the concept of off-target.