Canagliflozin: Who May Benefit From New Diabetes Drug?

Anne L. Peters, MD, CDE


April 09, 2013

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Hi. I'm Dr. Anne Peters from the University of Southern California, and today I'm going to talk about canagliflozin, a drug just approved by the US Food and Drug Administration (FDA). Canagliflozin is from a new class of drugs for the treatment of type 2 diabetes. It's known as an SGLT2 inhibitor, which stands for sodium glucose cotransporter 2. Basically, it is involved in the reabsorption of glucose from the kidney.

People with type 2 diabetes actually reabsorb glucose too much, and that's partly how they become hyperglycemic. When you give them an SGLT2 inhibitor, you interfere with some of this glucose absorption, so a patient starts to lose glucose in their urine. In essence, they become a bit glycosuric. When this happens, serum blood glucose levels fall and, to some degree, weight also falls because people are losing more calories in their urine.

When I first heard about this mechanism, it kind of struck me as odd given that I trained in the day when we sometimes used urine glucose testing. But here, it appears to be a favorable mechanism of action because it's lowering the glucose levels in the blood. Canagliflozin, which is the generic name, is known by the trade name Invokana. Don't quote me on how to say that, because I'm not quite sure, but you will see it marketed as such. For the moment, though, I'm going to talk about it as canagliflozin because that's how I've been referring to it in the past.

Canagliflozin comes in 2 different pill sizes: a 100-mg tablet and a 300-mg tablet. Patients should take it first thing in the morning before breakfast. As an analogy, I think of giving this drug a little bit like using a diuretic, because it is going to make them a little bit glycosuric and it will have a little bit of a diuretic effect. So, you want them to take it in the morning so they don’t urinate all night long when they're getting used to it. You will start patients at 100 mg. If that dose is tolerated you can uptitrate to 300 mg, and that's the dose the patient continues on.

In terms of what you'd expect using this drug, it's been studied in almost all combinations, and you can see all of this data in the package insert. It's been studied as monotherapy and in combination with metformin, sulfonylurea agents, thiazolidinediones, and an insulin. The reduction in A1c level varies among the studies, but it's between 0.5% and 1%, averaging around 0.7% and 0.8%. There's also an accompanying weight loss -- again, that varies. It's generally somewhere between 2% and 4.8% of the total body weight.

There are a number of caveats to using this drug, and I think it's important that people read about them and learn them, because it is a new class of drug. For instance, you should not use this drug in patients with significant renal insufficiency. If the estimated glomerular filtration rate (eGFR) is < 40 mL/min/1.73 m2, don't use this drug. If the eGFR is between 45 and 60 mL/min/1.73 m2, you may not want to uptitrate to the full 300-mg dose. This drug can cause a number of electrolyte abnormalities, particularly hyperkalemia, so you want to make sure you follow the potassium level when you are starting your patient on this drug.

Now, one needs to use this drug with a little bit of caution in patients who are already on diuretics and/or an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Again, I think you need to look at it this way: If you have a patient whose blood pressure is low, who already has orthostatic hypotension, and who at baseline is already a bit dehydrated, you might not need or want to give this drug. As with anything, you'll want to assess individual patients.

Other side effects are possible. The ones most notable, in terms of the drug development, were a number of genitourinary side effects. The most significant side effect was an increase in mycotic vaginitis in women, and that occurred in about 10% of women in the clinical trials. It can also cause urinary tract infections, and the rate of that is around 5%. And it can cause mycotic balanitis in men. That rate was somehow lower, though, at around 3% of the patients studied. You may want to warn patients of this, so that if they develop either a urinary tract infection or a vaginal or genital infection, they can let you know and you can treat it appropriately.

Initially there was a concern about a worsening in cardiovascular events, particularly an increase in stroke. When the FDA evaluated the data, however, they didn't feel that this was significant. However, if you have a patient who develops orthostatic hypotension when they start on this drug, or if the patient is dizzy, you might want to assess their blood pressure and make sure they are doing alright.

The FDA has required the drugmaker to do 5 big ongoing studies post-approval, and the largest of these is CANVAS, a cardiovascular outcomes study. It was started in 2009, so they have something of a head-start on getting data in terms of cardiovascular outcomes. We will see how this proceeds over time.

In summary, we have a new drug on the market, canagliflozin, with a new mechanism of action. I think it's important to tell your patients that there may be new and unknown risks to this drug. There also may be benefits that we don’t quite know, and we'll all see how we like it when we use it in our patients with diabetes. This has been Dr. Anne Peters for Medscape.