In this section, we're going to cover the newest drugs in diabetes treatment.
These are called the SGLT2 inhibitors.
They are an entirely new class of drugs that came onto the scene,
perhaps five or six 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 two 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 into the glomerulus in the blood
and get 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's 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.
Though you still have minimal glucose excretion
which tells us that the kidney is working properly.
If the amount of sugar coming into the nephron is too much for the two ports,
you have increased glucose excretion via the urine.
In other words, glucose urea.
Now, normally in diabetes, when we see sugar in the urine,
we see that as a failure of the kidney to keep up with the high blood sugars
and we see it as a failure of sugar control.
So, generally speaking, up until the time that 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 you're not reabsorbing sugar from the proximal convulated 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 first.
In fact, the first time we've ever seen SGLT2 and 1 inhibitors was is 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 Marian 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 anti-diabetic effect.
Now, we have many SGLT2 inhibitors that are available.
The one that failed was called phlorizin 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 canigliflozin which was the first 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 first to come onto the market.
We have many more that have appeared on the market since then.
I won't go into the particular 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 then say, dapagliflozin or empagliflozin.
So, when we saw that canagliflozin was seen to be associated with more fractures or other side effects,
we thought this might be related to the ratio of the two products.
Nevertheless, all of these products have shown some significant promise going forward.
Increasing the amount of sugar in urine comes with a price
and that is a three-fold increase in both bacterial and fungal urinary tract infections.
In women, that can be up to 10% of all patients
who develop some kind of a urinary tract infection, either fungal or bacterial.
Hypoglycemia is certainly a concern.
It's almost nonexistent 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 wanna 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 in diabetes.
In fact, there's a trial going on right now with one of my colleagues
looking at using these drugs with EGFR values less than 15.
Every year, we're reducing the bottom level EGFR recommended for therapy.
Right now, it's sitting around 30 with most recommendations
but we have new studies coming out and you should keep your eye to the--
you should keep your eye on the literature going forward.
With the newer SGLT2 inhibitors, there are rare GI complaints but they are present.
People will often complain of abdominal bloating or gasiness.
In terms of the positive effects, we have several studies with Farxiga--with Farxiga,
pardon me, with the 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 renoprotective 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, a mitigation of deterioration.
We have seen evidence of some anti-hyperlipidemic effects.
How important that is in the real world, we don't know yet.
We have seen some evidence of anti-atherosclerotic effects,
we've 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 the 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.
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.
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's 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're recommending that we don't use these medications with Lasix or furosemide.
So, you have to be careful with using them in diuretics.
I've had several patients have serious reactions
when they were already on a hydrochlorothiazide diuretic and they replaced on an SGLT2.
I've seen renal function crash 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 in using SGLT2 in these patients. Finally, the sick 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 they're at risk of renal failure
because of dehydration and the combination of the pills.
Another thing I wanna 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 sugar is normalized
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.