Diabetes Forecast

New SGLT-2 Meds Target the Kidneys

By Erika Gebel, PhD , ,

French chemists first discovered an SGLT-2 inhibitor in the bark of an apple tree back in 1835.At the time, they couldn't have known they'd found the precursor of a class of medications that would become a new diabetes treatment almost 180 years later. In spring 2013, canagliflozin (Invokana) became the first SGLT-2 inhibitor to receive Food and Drug Administration clearance for sale in the United States.

This new option for people with type 2 diabetes has some enticing qualities, such as weight loss and a low risk of hypoglycemia, but it's important to be aware of potential side effects, too. Consider this your meet-and-greet with the newest member of the diabetes medication clan.

Shift in Focus
Until SGLT-2 inhibitors, diabetes medications were mainly about insulin, the hormone that helps the body absorb glucose from the blood for fuel. Primary diabetes medications have traditionally worked through some combination of encouraging the pancreas to produce more insulin, increasing the body's sensitivity to insulin, and providing insulin from outside the body. The SGLT-2 inhibitors target the kidneys, lowering blood glucose by sending excess sugar into the urine.

You may be wondering what exactly the kidneys have to do with blood glucose in the first place. Quite a lot, it turns out. The kidneys are the body's filters. As blood passes through them, the kidneys decide which blood components stay and what gets excreted in the urine. In a healthy person with normal blood glucose levels, all the glucose is reabsorbed and stays, says Rebecca Rosenwasser, PharmD, a postdoctoral fellow at the East Coast Institute for Research.

Ninety percent of the glucose that gets reabsorbed from the kidneys is through SGLT-2, or sodium-glucose cotransporter 2. This protein looks something like a little tunnel, and there are many of them embedded in the walls of kidney cells. When the protein tunnels are open, glucose that has been filtered through the kidneys can travel back into the bloodstream.

Reabsorbing glucose is usually a good thing because it prevents the kidneys from draining off precious nutrients. But the kidneys of people with type 1 or type 2 diabetes may go overboard. Rosenwasser says people with diabetes have a higher than normal concentration of SGLT-2 proteins in their kidneys. Instead of letting some of their excess blood glucose spill over into the urine, they are reabsorbing more than they should, contributing to high blood glucose. So why not close these gates to keep excess glucose from returning to the bloodstream? Well, that's the general idea behind SGLT-2 inhibitors.

New Meds

These three SGLT-2 inhibitors are on the U.S. market. The FDA has asked for post-market studies to look at cardiovascular outcomes and other safety issues (the medications are currently indicated only for adults with type 2 diabetes). At least eight more SGLT-2 inhibitor investigational medications are at earlier stages.

On May 15, 2015, the FDA warned that use of SGLT-2 inhibitors may, in rare cases, lead to ketoacidosis, in which harmful levels of ketones (a type of blood acid) may build up in the body. This may happen even without high blood glucose levels. Do not immediately stop taking SGLT-2 inhibitors because of this warning, but do discuss the risk with your health care provider and create a plan for avoiding ketoacidosis, including having urine or blood ketone strips available. Ketoacidosis is a serious medical condition that requires hospitalization. Too little insulin and dehydration are other factors in diabetes ketoacidosis. Be aware of ketoacidosis symptoms: difficulty breathing, nausea, vomiting, abdominal pain, unusual sleepiness or fatigue, and a fruity odor on the breath. 

Canagliflozin (Invokana)
Janssen (Johnson & Johnson companies)

Dapagliflozin (Farxiga)

Empagliflozin (Jardiance)
Boehringer Ingelheim, Eli Lilly & Co.

Shutting It Down
The first clues that SGLT-2 might make a fine target for a new diabetes medication came from a rare genetic disease called familial renal glucosuria, says Rosenwasser. People with the condition are basically fine, but they have glucose in their urine and blood glucose levels that are slightly lower than normal, though not low enough to be classified as hypoglycemia. Genetic studies revealed that the condition is caused by mutations in the gene for SGLT-2. This suggested that SGLT-2 could safely be turned off, lowering blood glucose without causing hypoglycemia. That made it "a good target" for new diabetes medications, says Rosenwasser. What scientists needed was a way to turn off SGLT-2 in people without familial renal glucosuria.

Drugmakers started hunting for chemicals that shut SGLT-2 down, blocking glucose's path from the kidneys back into the blood and forcing excess glucose into the urine. That's where the SGLT-2 inhibitor discovered in apple tree bark enters the story. It's called phlorizin and, in the 1930s, researchers found that this chemical makes people excrete glucose without causing low blood glucose, just as happens in people with familial renal glucosuria. Eventually, over several decades, experiments showed that phlorizin inhibits SGLT-2. Phlorizin is part glucose molecule, which is how it tricks SGLT-2 into grabbing it. But instead of passing through the SGLT-2 tunnel, phlorizin lodges itself in the transporter, closing the way to glucose.

While experiments showed phlorizin could lower blood glucose in diabetic animals, there were problems. As its name suggests, SGLT-2 isn't the only sodium-glucose cotransporter around. There's also an SGLT-1, and phlorizin shuts down both of them. "SGLT-1 is the major transporter in the gut," says John Gerich, MD, a professor at the University of Rochester, who has worked as a consultant for and received research grants from companies involved with SGLT-2 inhibitor development. "If you block that, you get diarrhea, so [phlorizin] is not useful as a medication." That realization sparked a race by several drugmakers to tweak phlorizin so that it would stick to SGLT-2 but leave SGLT-1 alone. Canagliflozin and the other SGLT-2 inhibitors in development do just that.

Promise and Precautions
The test of any diabetes medication is whether it can lower blood glucose enough to improve health and is safe. The SGLT-2 inhibitors have a solid track record of lowering blood glucose when tested in people with type 2 diabetes. Taken once daily by mouth, SGLT-2 inhibitors lower A1C (average blood glucose over the previous two to three months) by an average of 0.7 to 1 percentage point. Because they don't rely on insulin to work, SGLT-2 inhibitors could be a suitable addition to insulin therapy for people with type 1 diabetes, who can't make insulin. Studies of the medications in people with type 1 are underway.

This class of medications appears to have some side benefits, too. As noted, blocking SGLT-2 doesn't lower blood glucose so much as to cause hypoglycemia, and that's true of all the inhibitors in this class. Plus, people taking SGLT-2 inhibitors have been shown in studies to lose between 4 and 9 pounds on average. "These drugs can cause excretion of as much as 60 to 80 grams of glucose per day," says Gerich. "At 4 calories per gram, that's about 300 calories." So weight loss isn't a surprise.

What was a surprise, and is still not fully understood, is that SGLT-2 inhibitors lower systolic blood pressure (the top number) by an average of 3 to 5 mmHg. The effect is even more dramatic among people with high blood pressure (hypertension). In them, SGLT-2 inhibitors bring blood pressures down by around 13 to 17 mmHg. "That's equivalent to a blood pressure medication," says Rosenwasser. The blood pressure reduction is not associated with either body weight or blood glucose control, so how it happens is unknown.

There are also concerns with SGLT-2 inhibitors. There have been reports of serious diabetic ketoacidosis events in a few type 2 cases and in people with type 1 diabetes using SGLT-2 inhibitors off label ("New Meds," right). The most common side effect of SGLT-2 inhibitors is genital tract infections. Urinary tract infections are a problem, but "the main concern is yeast infections," says Rosenwasser. "Glucose basically creates a good growing environment." So when extra glucose sits in the bladder, yeast may flourish. The drugs also won't work as well in people with kidney disease because they rely on well-functioning kidneys to excrete glucose.

SGLT-2 inhibitors tend to increase levels of LDL ("bad") cholesterol, which is troubling because people with diabetes are already at heightened risk for heart disease. "You never want a diabetes agent increasing an LDL," says Rosenwasser. However, Gerich says that if "you plug in what happens on these agents—lower blood glucose, lower blood pressure, and increased LDL—into an equation that calculates cardiovascular disease risk, you come out with a net benefit."

Other concerns: The FDA questioned whether dapagliflozin increases the risk for developing breast and bladder cancers. Some SGLT-2 inhibitors raise markers of bone degradation, says Rosenwasser, though apparently not fracture risk. Some scientists are concerned that canagliflozin may raise the risk for heart disease. Regulators will continue to monitor these issues after the medications are on the market.

As with all medications, doctors and patients must weigh benefits against risks when deciding what treatments to try. "We don't have the ideal drug yet to treat diabetes. All of the drugs have good points and bad points," says Gerich. And he, for one, is looking forward to having one more tool to help treat people with diabetes.

Edited May 19, 2015.



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