SGLT2 Inhibitors – Diabetes Medications

by Pravin Shukle, MD

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    00:01 Let's move on to the SGLT2 inhibitors. This is actually really quite exciting so it's going to really change the way we treat diabetics I think in the future.

    00:11 Now, the normal human kidneys reabsorb about 180 g of filtered sugar each day.

    00:18 So that means that as you have sugar and blood going into the glomerulus, 90 % of it is going to get reabsorbed in the proximal convoluted tubule.

    00:29 Another 10 % is going to be absorbed in the descending limb of Henle.

    00:34 Now, we have porters that are responsible for pulling sugar out of the interstitial fluid, out of the intertubular fluid, and back into the blood. These are SGLT2 and SGLT1. So SGLT2 stands for sodium glucose transporter type 2 or type 1.

    00:58 Now the SGLT2 is responsible for 90 % of sugar reabsorption and SGLT1 is responsible for about 10.

    01:07 Remember that SGLT1 is also found in other tissues in the body, whereas SGLT2 is mostly in the kidney.

    01:16 When you have more sugar going in because you're hyperglycemic or you're diabetic, you're going to have a moderate amount of glucose excretion in the kidney in the urine because you're overwhelming the normal reabsorption capacity.

    01:30 But take a look at that reabsorption capacity with the blue arrow. It's much thicker than it was before which shows you that SGLT2 can actually reabsorb more than it is at base level.

    01:44 And when we give a person an SGLT2 inhibitor we're actually blocking the reabsorption at the first part of the proximal convoluted tubule.

    01:55 So, you end up having increased glucose excretion through the urine.

    02:00 Let's take a look at these drugs. Now, they've had a kind of a mixed history because in actual fact, the very first antiglycemic medication ever discovered wasn't insulin, it was actually phlorizin, and it was discovered way back in 1835 when it was isolated from the apple tree bark.

    02:17 And there's actually even theories or beliefs that the Egyptians may have used cherry tree bark as far back as 3,000 years ago.

    02:26 So, this may have been the very first antiglycemic medication.

    02:31 Phlorizin was then discovered and the glycosuric effect was discovered in around 1865.

    02:40 The mechanism was finally explained in rat models in 1903.

    02:45 By 1933, we actually discovered that they were present in humans as well, and we explained the mechanism in an important physiology journal.

    02:56 In 1987, the antidiabetic effect was really discovered or I should say re-discovered.

    03:04 And in 2008, the very first commercially available SGLT2 inhibitor was released, and then finally withdrawn because of severe side effects.

    03:18 Why was it withdrawn? Well, remember that the first agent had a lot of SGLT1 activity.

    03:25 And so when you had SGLT1 activity, you actually had side effects including severe abdominal discomfort.

    03:32 The newer drugs are much more specific to SGLT2. There are really three drugs out there on the market right now.

    03:39 Canagliflozin, dapagliflozin, and empagliflozin.

    03:46 Now, there is some adverse events associated with it. We have a 3 fold increase in bacterial and fungal urinary tract infections, and that may be up to 10 % of all females taking this medication. It's a little bit lower in males.

    04:00 Hypoglycemia is almost nonexistent with monotherapy. And why is that? That's because the SGLT2 inhibitors aren't really that active with normal sugar levels.

    04:12 Now, we are not currently recommending them in renal failure but I'm actually taking part in the study that's looking at using these medications in low to moderate renal failure.

    04:22 There are some studies to suggest that the SGLT2 inhibitors may be renally protective, and in fact may be good for patients with mild renal impairment.

    04:33 At this point in time, our knowledge isn't there yet. There may be studies that come out in the future, perhaps in 2017 or 2018, which is when we're expected to publish the results.

    04:44 There are rare GI complaints from this medication although they are there.

    04:51 Volume depletion, use with caution in patients who are already on diuretics.

    04:55 So, I've had a couple of patients who are on hydrochlorothiazide, and when we added the SGLT2 inhibitor, their renal function crashed. So be very cautious with this.

    05:04 And in fact, two of the drugs are contraindicated with concurrent use with furosemide.

    05:09 So, it's a very important consideration and not want to be taken lightly.

    05:14 Patients who are elderly may be hypovolemic, and they may not benefit that much from the SGLT2 inhibitors and you could put them at risk.

    05:22 Remember that sick rules apply. So whenever we have patients who are sick, nausea, vomiting, unable to keep down fluids, we want to get rid of drugs or hold drugs or not take medications that are responsible for either diuresis or reduction of blood pressure.

    05:38 So, if they have a really bad stomach flu, do not continue the medications, stop it until they're better.

    05:45 Now, I want to talk to you about ketoacidosis. This is an important consideration.

    05:50 It hasn't yet made it out into the literature, but I think by the time we roll around December 2016, it'll be out there.

    05:57 Ketoacidosis is a very important consideration. Remember that when you have a thin young man or thin young woman coming in, and their sugars are 25, 26, 27, they need insulin because you need to stop the metabolic freight train that is running through their body.

    06:15 Sometimes, doctors are giving these medications with the belief that we don't need to give them an injection that we can give them a pill to help get rid of the sugar.

    06:24 The problem is is that you're not treating the acidosis, and insulin is treating ketoacidosis too, it's not just treating the sugars. So I think that we may end up seeing more events of ketoacidosis if we use these medications in place of insulin in acute situations.

    06:41 There are some studies that are going on, I bet you a dollar that by the time you read or you listen to this video, there is going to be information out there about ketoacidosis. I think it will be very important.

    06:52 And we're going to say "Okay, thin young people who are showing up in the ERs, give them insulin first, get them stabilized, then try them on SGLT2 agents later when they are stable."

    About the Lecture

    The lecture SGLT2 Inhibitors – Diabetes Medications by Pravin Shukle, MD is from the course Endocrine Pharmacology. It contains the following chapters:

    • SGLT2 Inhibitors
    • SGLT2 Inhibitors – Adverse Events

    Author of lecture SGLT2 Inhibitors – Diabetes Medications

     Pravin Shukle, MD

    Pravin Shukle, MD

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