There are new drugs in diabetes town. The SGLT2 inhibitors work in the kidneys. They cause glucose to leave the body through the urine. Presto — blood glucose comes down. Could there be any disadvantages to this approach?
The kidneys work with glucose all the time. They have several ways of keeping glucose levels up. Kidneys make glucose by breaking down the starch called glycogen. They create new glucose from chemicals like lactate and glycerol. Kidney parts called nephrons absorb glucose from the urine and put it back into the blood.
This is all good for most people, because it preserves glucose, our body’s main fuel. But what if there’s too much glucose in your blood already? For people with diabetes, the kidney’s “reabsorbing” glucose can be a big reason for high blood glucose levels. Here’s how it works.
When blood passes through the kidney, glucose, along with waste products, is filtered through structures in the nephron known as glomeruli. In the nephron, proteins called glucose transporters grab the glucose and move it back into the blood.
One of the main transporters is SGLT2. SGLT stands for sodium-glucose cotransporter. Glucose needs transporter molecules to get into and out of cells. Many of these transporters use sodium to glide through cell walls.
Because of SGLT2 action, most people have no measurable glucose in their urine. Glucose in the urine is called glycosuria. It happens where there is too much glucose in the blood for the nephrons to reabsorb.
Glycosuria usually happens when blood glucose gets above 180 mg/dl (10.0 mmol/l). Because 180 is a high level, glycosuria is considered a sign of diabetes being poorly controlled.
That’s where the SGLT2 inhibitor drugs come in. When SGLT2 is blocked, glucose won’t reabsorb, even when blood glucose levels are much lower than 180 mg/dl. It gets urinated out, and blood levels stay closer to normal. There is even evidence of beta cell regrowth in diabetic rats taking an SGLT2 inhibitor.
Very clever of our scientists to bring the kidneys into the diabetes picture. Other drugs work on the pancreas, liver, or intestines, but if we’ve got extra glucose in our blood, why not just urinate it out?
The SGLT2 inhibitors have a number of positive effects. They cause weight loss, because glucose that’s lost in urine can’t turn into fat. They seem to lower blood pressure, probably because sodium is lost along with glucose. They increase levels of HDL (“good” cholesterol.)
There are downsides, though. According to an article in Medscape, SGLT2 inhibitors also seem to raise LDL (“bad” cholesterol.) Also, by putting sugar in the urine, they raise the risk of bladder infections and vaginal yeast infections.
Writing in Diabetes Self-Management, Jennifer Goldman-Levine, PharmD, CDE, BC-ADM, FCCP, listed hypotension (low blood pressure) and long-term kidney problems as possible negative effects of Invokana, the first approved SGLT2 inhibitor.
There is some concern about risks of cancer. In 2012, the FDA turned down the first SGLT2 inhibitor, called dapagliflozin, because of an increase in bladder and breast cancer among users.
It’s also not clear what the long-term effects on heart disease and stroke will be. In one study, the rate of cardiac events were up at the beginning of SGLT2 inhibitor therapy compared to placebo (inactive treatment), although the rates evened out after a month.
One other concern we know about — these drugs cost over $9 per tablet. Even at Walmart, Invokana costs $282 for 30 pills.
Then there are the concerns we don’t know about. Vioxx (generic name rofecoxib) was a “miracle” pain killer. Merck released it in 1999. About 80 million people took it, even at brand name prices. Then it turned out to cause heart attacks and stroke. It was withdrawn from the market in 2004 after being implicated in between 88,000 and 140,000 cases of serious heart disease, including thousands of deaths.
Vioxx is relevant to the SGLT2 inhibitor story. Vioxx was a “COX-2 inhibitor.” COX 1 and 2 are parts of the inflammatory response. Other anti-inflammatory drugs (NSAIDs) block both COX 1 and 2, but this sometimes causes stomach ulcers. By blocking COX 2 but not COX 1, Vioxx protected stomachs while relieving pain.
Unfortunately, COX-2 also has some important effects in protecting blood vessels. When COX-2 is inhibited, there is more blood clotting. It took years for these effects to show up as heart attacks and strokes.
Something similar could happen with SGLT2 inhibitors. You can’t just block it in the kidney; these drugs block SGLT2 everywhere. SGLT2 transports glucose from the intestines to the blood, and there may well be some other SGLT2 functions that we don’t know about, but wouldn’t want to block.
Many doctors who support SGLT2 inhibitors admit that we need a longer time to evaluate benefits and risks and how long the benefits will last. More studies are being done to gain this information.