Updates on SGLT2 Inhibitors

A completely new class of diabetes drugs came out in 2013, called SGLT2 inhibitors. Now they are widely used, but how well are they working? Should you take them?

A lot of researchers are studying these drugs, also called “SGLT2-is” or “gliflozins” (glif-FLOW-zins). The 2016 ADA Scientific Sessions featured nearly 100 presentations on them.


“SGLT2” stands for sodium-glucose cotransporter 2, a class of proteins that attach to glucose. SGLT2 works in the kidney, moving glucose out of the urine and back into the bloodstream. It does this so that sugar is not wasted in the urine.

Our bodies evolved not to waste sugar. There wasn’t enough food around to waste any in the urine. In diabetes, however, it would be nice if people could lose excess sugar in the urine, but SGLT2 keeps that from happening unless sugar levels are around 200 mg/dl or higher.

SGLT2 inhibitor drugs keep glucose in the urine from being reabsorbed into the blood. Glucose gets peed out, lowering blood sugar. Because calories are lost with the sugar in the urine, these drugs also cause some weight loss. They seem to slightly lower blood pressure as well.

There are currently three SGLT2 inhibitor drugs on the market in the United States — canagliflozin (brand name Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). It seems they all work about equally well. Because the drugs are so new, the longest studies we have only lasted a few years.

What are the risks?
So far, gliflozins look pretty safe. No major drug–drug interactions or drug–food interactions have shown up. They have been found safe for the liver, as they are apparently not processed in the liver like most drugs are. There is an increased risk for urinary tract infection and vaginal infection because the extra sugar in the urine helps germs grow, but these can be prevented and managed.

Although the drugs seem to slow the progression of kidney damage, they do make the kidneys work harder. So people with advanced kidney disease should avoid them or take lower doses, according to this French study.

Gliflozins can cause dehydration. Passing glucose in the urine takes a lot of water with it. You need to drink more fluids and might need to be careful not to faint when you stand up, particularly if you are older.

The Food and Drug Administration has warned of an increased risk of diabetic ketoacidois (DKA), a life-threatening buildup of acids in the blood, associated with these medicines (particularly in people with Type 1 and those with Type 2 using insulin).

DKA usually happens because you don’t have enough insulin, so glucose can’t be used as fuel. The body starts to burn fat, and acidic molecules called ketones are byproducts of this process. Too many ketones will make your blood too acid, which can shut down your entire body.

Normally, you would see DKA coming because your glucose levels would be very high. But gliflozins can mask the high glucose by sending it to the urine. People on gliflozins can get DKA with almost normal blood sugars. There have been over a hundred cases like this in the U.S. and Europe in the last five years. Some doctors strongly advocate that people with Type 1 not take a gliflozin because of this risk, and the medicines are only approved for use in adults with Type 2 diabetes in the United States.

Insulin users may get in trouble because doctors may lower their insulin dose. They do this because sugar levels on gliflozins may not be high. But insulin is still needed to keep the liver and fat cells from making ketones. Add that to dehydration potentially caused by gliflozins, and you can wind up in the ICU.

According to Medscape, “Contributing factors [to DKA] included recent illness, increased exercise, decreased food intake, and alcohol consumption, although a few patients had no identifiable contributing factors.”

If you take an SGLT2 inhibitor, you should be aware of the symptoms of ketoacidosis. The Food and Drug Administration advises, “Patients should…seek medical attention immediately if they experience symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness.”

Surgery is a major risk for DKA on a gliflozin. Simeon Taylor, MD, PhD, professor of medicine at University of Maryland School of Medicine, suggests stopping SGLT2 inhibitors three days before elective surgery, according to Medscape.

What are the benefits?
Studies presented in New Orleans reported that canagliflozin lowered HbA1c about 1% on average. It increased the amount of time each day people with Type 1 spent in the normal glucose range (more than 70 to less than 180 mg/dl).

Canagliflozin also promoted weight loss of about 2 to 4 kilograms (4.4 to 8.8 pounds) on average. I wonder how much of this is lost water weight, though.

More significantly, it slowed the decline in kidney function at varying degrees of kidney health. A study from the Netherlands cited on Diabetes in Control concluded that the “beneficial effect on kidney function is independent of its [effects on sugar].”

In another study, dapagliflozin was used in combination with a water pill (diuretic) and lowered HbA1c, body weight, and blood pressure.

Gliflozins are not generic and may cost over $10 per tablet. If your insurance doesn’t cover them, that’s roughly $400 a month, but coupons and manufacturer assistance programs are available.

Clearly, SGLT2 inhibitors have many benefits and some risks. If you take them, make sure to stay hydrated, guard against vaginal and urinary tract infections, and know the signs of ketoacidosis.