SGLT2 Inhibitors: Behind The Curtain

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You may not be familiar with the term SGLT2 inhibitors, but you may have heard about this new class of drug, it's that stuff that you take that causes you to pee out sugar, the way you do when you have very high blood sugar that exceeds your renal threshold.

The list of brand names that are included here are Invokana, Farziga, and Jardianse, with both Invokana and Farzinga being also available with added metformin, and Jardianse also combined with a DPP-4 inhibitor.

Your kidneys normally reabsorb glucose, instead of excreting it in your urine, which is to actually preserve the glucose in your blood.  The job of the kidneys is to filter your blood and they decide that they want to preserve the glucose in there unless there's simply way too much, and their excreting it is a protective mechanism against extreme hyperglycemia, although your blood sugar can be very high even though you may be urinating quite a bit out.

So what this class of drugs do is trick the kidneys into thinking that they need to start filtering out glucose, at levels that are of course below the normal renal threshold, to look to use this safety valve to reduce blood sugar to levels normally not achievable by this mechanism.

So on the surface this seems like a pretty decent idea, and given that there is too much glucose in the blood of the target patients, type 2 diabetics who are not able to achieve good enough glycemic control on their own, it seems preferable to pee it out then to metabolize it, under the assumption that there is simply too much there to metabolize without causing further problems, like for instance with insulin resistance.

So if insulin levels are at least normal, and we would hope that if they were below this patients would be put on insulin therapy, metabolizing all this extra glucose with higher than normal insulin levels is at the very least going to worsen insulin resistance, and if we can just pee it out instead well that's at least not worsening the major problem with us.

The first question that comes to mind for me is that if the kidneys do not feel it necessary to excrete it, should we be messing around with their function to encourage it to act so unnaturally?  This may seem like a silly question when you first see it but it may indeed be that, in our present state, we require this higher blood sugar to promote overall bodily functions, and the real answer to solving this may be to look a lot harder at why this seems to be the case, and look to address that instead.

In any case, there is a price in doing this, and one of the things that this causes is infections of the urinary tract, especially fungal infections, and fungus loves sugar.  We are turning the urinary tract into a sugar den actually, and sugar does not belong here, so there are consequences.

This isn't a reason to not use the med though, if the benefits outweigh the consequences, and there isn't something else we could be doing instead which would provide a bigger net gain, where net gain here is defined as benefits minus costs, it still can be worth it.

So one's susceptibility to UTI infections is going to depend on the patient, as some are more prone to this then others, both in frequency and severity.  There's other side effects of course, and side effects must also be taken into account, especially to the degree they present themselves during treatment.

The FDA has very recently become concerned with a far more serious side effect, as the drug has gone from trials to being widely prescribed, and this concern is about the potential of these drugs causing diabetic ketoacidosis, a life threatening condition, the same one that metformin involves, although the risk is virtually nil with metformin, and we'll have to see how the risk with the SGLT2 inhibitors plays out as they look into this further, but this is worth keeping an eye on.

What's also very interesting is the fact that SGLT2 inhibitors directly increase glucagon secretion by the alpha cells of the pancreas, which is said to be the main reason why this class of drugs does not reduce blood sugar more than it does, which so far has been only an average of a 0.75% reduction in A1C among users.

That's still not bad, but some people wonder how you could only reduce blood sugar by this relatively small amount, especially compared to some orals which can reduce it twice this much, when you are peeing out huge amounts of glucose.

By increasing glucagon though, you increase hepatic glucose production, and we tend to have way too much of this going on already, without having it cranked up even further.  The important thing to be aware of here is that depending on how much extra hepatic glucose production one is already disposed to, the results will probably vary, where the net glucose removed from the blood, when you take what's been removed minus the extra this has created, may be small enough to not want to bother with.

Of course dietary control probably helps this out a lot as well, ingesting less glucose for instance, although that's not generally part of the treatment of diabetes, sadly.

There are some patients I've heard from who really like this drug, and it seems to help them, it's a new drug though and we'll have to keep a close eye on how the real world trial pans out over time.

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