Working to improve a promising new diabetes drug

A new type of drug that has been the focus of much study by San Antonio researchers takes a fairly straightforward approach to treating diabetes.

It sends excess sugar down the drain. Literally.

Over the past two years, three different oral drugs in a class known as SGLT2 inhibitors have been approved by the U.S. Food and Drug Administration — and more are on the way, said Dr. Eugenio Cersosimo, associate professor of medicine at the UT Health Science Center, and clinical research director at University Health System’s Texas Diabetes Institute.

While the liver, pancreas, muscle and fat cells all work to regulate blood sugar, the kidneys also play a role. While some excess sugar is eliminated from the body through urine — in fact, for centuries diabetes was diagnosed by how much sugar was present in urine — it turns out that the kidneys also recover most of that sugar before it leaves the body and return it to the bloodstream.

How much sugar?  A lot, it turns out.

“If you have normal blood sugar, you reabsorb 180 grams every day — or about a pound every three days,” Dr. Cersosimo said. “The diabetic has twice that much, because they have a lot more sugar in the blood. So the kidney enzyme works twice as hard to reabsorb the sugar.”

The kidney uses an enzyme called sodium-glucose co-transporter 2, or SGLT2, to capture and transfer the sugar back to the blood. One theory is that this process evolved so that the body could maintain its energy supply of sugar even when food was scarce. But in people with diabetes, the phenomenon only makes things worse.

Dr. Ralph DeFronzo, chief of the Diabetes Division at the UT Health Science Center, and deputy director of TDI, was among the first decades ago to study a substance made from apple tree bark that proved to block SGLT2 in animals. While it improved diabetes, it was too toxic to use.

Since then, researchers have been altering SGLT2 inhibitors in the lab to make them less toxic and more effective. The first to reach the market was canagliflozin, sold under the brand name Invokana and approved in March 2013. Last year, two more were approved: Farxiga and Jardiance.

Not only are the drugs effective in reducing blood sugar levels, they have an added benefit by simply eliminating the hundreds of calories contained in all that sugar: patients tend to lose weight. The biggest side effect was a higher risk of urinary tract infections. Studies on any long-term effects are ongoing.

TDI took part in some of the early clinical trials of SGLT2 inhibitors, and continues to study them now  in combination with other diabetes medicines. But just as importantly, Drs. DeFronzo, Cersosimo and their colleagues continue to study the mechanisms of how the drugs work, with an aim to improve them.

“We know it’s a good drug,” Dr. Cersosimo said. “It works. It has minimal side effects, but they’re acceptable also because of its effects on sugar and body weight. But how much (more) can we block the enzyme? We’ve shown so far we can block 50 percent of it. It could be improved.”

Photo courtesy Pixabay

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