00:00
In this section, we're going to cover the newest drugs in diabetes treatment. These
are called the SGLT2 inhibitors. They're an entirely new class of drugs that I came
on to the scene perhaps 5 or 6 years ago but they have a long history. Now, when
you look at the kidney and how glucose is reabsorbed from the nephron, you can
see that it goes through 2 major ports. The first one is called the SGLT1 that is
illustrated here in pink and the second one is called the SGLT2 that is illustrated in
blue. Sugar or glucose comes in to the glomerulus in the blood and gets picked up
or sucked out of the nephron by either SGLT2 or SGLT1. You can see that the 90%
of the sugar being reabsorbed from the proximal convoluted tubule is done through
SGLT2 and about 10% is done through SGLT1. Another important thing to know about
these drugs is that the SGLT1 receptor is found all over the body. The SGLT2 tends
to be more localized in the kidney. So it makes sense with our drugs that are acting
on these ports that we want something that is more specific for SGLT2. Now when
we have active SGLT1 and SGLT2 ports, you can see that the amount of sugar going
out in the urine is quite minimal so there is minimal glucose excretion shown by
the small arrow in yellow. Now, let's suppose that a person has elevated blood
sugar levels or hyperglycemia. When you have hyperglycemia, you have increased
glucose reabsorption that's occurring both at the SGLT2 and to a lesser extent the
SGLT1 port. Do you still have minimal glucose excretion which tells us that the kidney
is working properly. If the amount of sugar coming in to the nephron is too much
for the 2 ports, you have increased glucose excretion via the urine, in other words
glucosuria. Now normally in diabetes when we see sugar in the urine, we see that is a
failure of the kidney to keep up with the high blood sugars and we see there's a
failure of sugar control. So generally speaking up until the time of the SGLT2 inhibitors,
we thought that elevated urine sugar was a pathological real problem. Along come the
SGLT2 inhibitors. What they do is they take a person who has this massive amount
of glucose reabsorption and stop it. So now what happens is that urine not reabsorbing
sugar from the proximal convoluted tubule and you see a large amount of sugar going
out into the urine. This is what SGLT2 inhibitors are doing and that's the basic
mechanism on how they work. Now typically, we talk about SGLT2 inhibitors as being
the newest in the drug classes treating diabetes but in actual fact it's probably one
of the firsts. In fact, the first time we've ever seen SGLT2 and 1 inhibitors was in
1835 and it was isolated from the apple tree bark. We knew then that it caused
increased sugar output in the urine. By 1865, we established that these particular
products cause the glycosuric effect. By 1903, the mechanism had been explained
in the rat model in a physiology lab in Philadelphia. By 1933, we saw the same
kind of mechanism seen in humans and we were able to say "Well, it's the same
as the mirian model. We now have a point of entry for diabetic control." By 1987,
we discovered that not only did it cause glucosuria, but it also had an antidiabetic
effect. Now, we have many SGLT2 inhibitors that are available. The one that failed
was called fluorescein and one of the reasons why we think it failed was because
it had a lot of SGLT1 activity which had all kinds of implications in bone and in stomach
and in other organs. With the development of canagliflozin which was the 1st
of the modern era SGLT2s or second generation SGLT2s, we had a much higher
specificity to SGLT2 receptors and we had an effective treatment. We had other
ones that showed up later. These are commonly seen in the United States as Farxiga
and Jardiance, Invokana was the 1st to come out to the market. We have many
more that have appeared on the market since then. I won't go in to the particular and
difficulties of separating out each individual one, but I will say this. When you look at
canagliflozin, canagliflozin has a lower SGLT2 to SGLT1 specificity ratio than say
dapagliflozin or empagliflozin. So when we saw that canagliflozin was seem to be
associated with more fractures or other side effects, we thought this might be
related to the ratio of the 2 products. Nevertheless, all of these products have
shown some significant promise going forward. Increasing the amount of sugar in urine comes with a price.
Now, it's not currently recommended in severe renal failure, that is, with an eGFR of less than 20.
These drugs may actually help renal failure and diabetes.
05:33
Hypoglycemia is certainly a concern, it's almost non-existent in monotherapy but we have seen it in
polypharmacy where people are on multiple medications like insulin or say the
sulfonylureas in association with the SGLT2. I want to point out though that it's not
the SGLT2 that's causing the hypoglycemia. The fact is is that the SGLT2s are quite
effective at bringing down the blood sugars and those other drugs like say the
sulfonylureas keep working even in the presence of a normal sugar and so then you
get hypoglycemia. So, when you're using this practically speaking, if you get
hypoglycemia it's coming from one of the other drugs. Now, it's not currently
recommended in renal failure, but that's going to change very very quickly because
we have a lot of studies that are coming out showing that in fact these drugs may
help renal failure and diabetes. In fact, there is a trial going on right now with one
of my colleagues looking at using these drugs with EGFR values less than 15.
06:35
Every year, we're reducing the bottom level EGFR recommended for therapy.
06:42
Right now, it's sitting around 30 with most recommendations but we have new
studies coming out and you should keep your eye on the literature going forward.
06:55
With the newer SGLT2 inhibitors, there are rare GI complaints but they are present.
07:00
People will often complain of abdominal bloating or gassiness. In terms of the positive
effects, we have several studies with Farxiga, with empagliflozin or Jardiance,
with Invokana or canagliflozin. They have all shown some improvement in
cardioprotective effects either in randomized control trials or through real world
evidence. We also see evidence of renal protective effects. We don't know what
the bottom EGFR is going to be in terms of when we don't want to use these drugs,
but certainly we see an improvement in renal function over time or at least the
mitigation of deterioration. We have seen evidence of some antihyperlipidemic effects.
07:47
How important that is in the real world, we don't know yet. We have seen some
evidence of anti-atherosclerotic effects. We have seen some anti-obesity effects
because there is weight loss associated with peeing out up to 900 calories a day,
and finally there may be some anti-neoplastic effects that we're seeing in laboratory
studies but not in clinical studies yet. So, the science is constantly evolving on the
SGLT inhibitors, but it's very very impressive. This drug is now being paid attention
to by cardiologists so you know that this is something that's really important.
08:29
We think that the mechanism of action in terms of blood pressure reduction and in
terms of volume reduction may not necessarily be due to its diuretic effect.
08:39
It actually might be something that's happening right within the cell and the
intracellular acidic and basic milieu. We're not 100% sure yet, but there is a lot of
exciting research. I would say the majority of research right now is going into SGLT2
inhibitors when you talk about diabetes research. Other serious side effects with
this is volume depletion. So we have to be very careful using this drug in association
with diuretics. In fact, in some countries including the United States, they are
recommending that we don't use these medications with Lasix or furosemide.
09:13
So you have to be careful with using them in diuretics. I have had several patients
have serious reactions when they were already on a hydrochlorothiazide diuretic
and they were placed on an SGLT2 I have seen renal function crashed. So monitor
the kidney function. If they're on a diuretic, consider holding the diuretic or reducing
its dose and watch them very carefully. In the elderly, these patients are very
prone to volume depletion so be careful using SGLT2 in these patients. Finally,
the SIK rules apply. So if you look at one of my other lectures, you'll see this mnemonic
called SADMANS. It's now SADMANS with an S at the end and that's because
we added SGLT2 to the list of medications that we want to hold or reduce when people
are vomiting and can't keep fluids down and their risk of renal failure because of
dehydration and the combination of the pills.
When a patient is sick, they can easily become
dehydrated due to throwing up, diarrhea or fever.
10:14
Dehydration can stress the kidneys so certain
medications can cause problems.
Therefore, these medications should be temporarily paused and can be started again once the patient has fully recovered.
10:29
The medications to be cautious of during this
time are those listed on sadmans list.
10:34
The S is for Sulfonylureas, other secretagogues.
A as in ACE inhibitors.
10:40
D, Diuretics with special caution if prescribed for heart failure and Direct renin inhibitor. M, Metformin.
A, Angiotensin receptor blockers.
N, Nonsteroidal anti-inflammatory drugs.
And lastly another S for SGLT2 inhibitors, or flozins.
11:01
Another thing I want to talk about is ketoacidosis. Now, with ketoacidosis, I've told you before that ketoacidosis requires
treatment with insulin. The problem with ketoacidosis is this. Because the SGLT2
inhibitors were so useful in the treatment of high blood sugar, some physicians started
using them when really insulin should have been used. Those were the thin, young,
diabetic patients who ended up presenting with very high blood sugars, they were
inappropriately treated with an SGLT2 inhibitor and their sugars normalize but it
didn't treat the runaway metabolism, the ketosis that happens with certain types
of type 1 insulin deficiency or type 1 diabetes. So it's really important to be aware
that those young patients who come in with really high blood sugars and they're
sort of that first presentation and you're worried that they might be type 1 diabetics
and they may be at risk for ketoacidosis. Treat those patients with insulin, not with an
SGLT2 inhibitor. The mild diuretic effect of SGLT2 inhibitors can exacerbate the
ketoacidosis because of course ketoacidosis is worse in the presence of volume depletion.