Janet McGill, MD, an Endocrinologist at Washington University St. Louis talks about how type 2 diabetes drugs may be beneficial for patients with type 1 diabetes.
Interview conducted by Ivanhoe Broadcast News in May 2019.
Give me the basic overview of the differences between type 1 and Type 2 diabetes.
MCGILL: Type 1 diabetes is characterized by a rather profound insulin deficiency to the point that many type ones make no insulin at all. Some make a little bit. And some we catch while they’re still making some insulin. But the hallmark really is insulin deficiency.
And for type 2?
MCGILL: For type 2 it’s a highly variable disease process that may span the gamut of body shapes and sizes and insulin deficiency versus insulin that is high to meet demands of insulin resistance. But it’s really a more variable disease.
And the treatments for those two diseases are different.
MCGILL: Treatments are very different. In type 1 diabetes the number one treatment is replacement of the insulin that can no longer be made by the pancreas. In type 2 diabetes we attack it from a couple of different angles. One is reducing glucose production by the liver enhancing glucose uptake and sometimes we have to add insulin if it’s just not sufficient. So it’s a more variable disease. And we use a broader array of treatments.
And there’s more treatment options for Type 2s. Right? There’s a lot of different tools and technology for type 1 but really it’s insulin. That’s the only medication. And the only other drug that could been approved just didn’t get approved…
MCGILL: Correct.
This week right? That’s it. It’s this one drug.
MCGILL: Right. So you’re absolutely correct that in type 2 diabetes we have many choices. And many of them work well together. So we can apply three or four agents all with moderate benefits and really get a very significant glucose lowering effect.
For type 2s.
MCGILL: For type 2 diabetes.
And type 1 there’s different delivery. There’s injections and there’s a pump. But it’s the same drug. You’ve got to figure out how to make that drug work the best for you.
MCGILL: Right. Type 1 diabetes where as I mentioned, the big job is to replace insulin and to do it physiologically to try not to avoid low blood sugars and also avoid high blood sugars. And we have a variety of tools to use pumps and continuous glucose monitors different types of insulin. We have lots of things to use but it comes down to how to deliver insulin.
I never even thought about the possibility of using Type 2 drugs until I ended up at Barbara Davis in October doing a story out there on a drug that didn’t get approved. And I thought wait a minute. There’s type ones on type two drugs. Why would you ever need to do that?
MCGILL: Because type ones don’t make insulin they shared that one feature in common. Everything else is different. Some are thin. Some are heavier. Some have sort of other physiologic needs. So aside from not making insulin we find a variety of underlying physiology. And that’s what we’re beginning to address with the use of some of the type two drugs in patients with Type 1 diabetes.
Can you go through the different type 2s drugs how they can help or some that wouldn’t help at all?
MCGILL: Sure. Drugs that don’t help at all are So sofoloreos or gylinides that act on the beta cell. And if you don’t have a beta cell there is no point in using those drugs. However the other classes of drugs may have other sites of action. For example metformin is widely used and in type 2 diabetes it limits glucose released from the liver which makes you a little bit more insulin sensitive and has been tested in type 1 diabetes. What we know is that it reduces the insulin requirement a little bit. It improves glucose control a little bit. But the response is variable. So it may be appropriate for some patients with type 1 but maybe not all patients with type 1.
So what are the other ones that are out there that might help some type ones?
MCGILL: The group of drugs called DPP 4 inhibitors have actions.They have a very limited effect in type 1. We tend not to reach for those in patients with Type 1 diabetes. They’ve been tested. They don’t cause harm. The benefits are limited. So the other drugs that we consider more often are the GOP one receptor agonists. And these are given by injection either once a day or once a week. And what these drugs do is they have effects on the beta cell. They also have effects on Alpha cells but also other sites in the body. They may help reduce the appetite a little bit. They can be helpful for heavier patients. A1C does come down a bit. And they tend to work in that group of patients. But the patients that are thinner tolerate them less well. We have to be selective about patients that we consider the GOP one receptor agonist. And some get quite noticeably good results. But again it’s variable.
What’s is the common name for that?
MCGILL: The daily injection is Vic Tozer. The weekly are Bidurian Trulicidy and now Ozentbec.
OK. So there are a few different kinds in this class of drugs. But those are type 2. It’s not insulin. It’s an injection. But it’s designed for type 2.
MCGILL: Right. They’re not approved for type 1 diabetes. We have difficulty using them even when we think that they may be appropriate. But in patients who are able to use them we see some really excellent results. Patients taking higher doses of insulin doses come down a bit and blood sugars stabilize.
What is the other class of drugs that’s showing a little bit more promise for type ones?
MCGILL: Right. The last class of drugs are really quite interesting. The acronym is SGLT2 inhibitor. SGLT2 is a transporter in the kidney and it causes the glucose that goes into the kidney to be reabsorbed back into the body. If you block the transporter the glucose goes out in the urine. So you just simply lose glucose. And it’s completely independent of anything happening at the pancreas or the beta cell. So in many respects it looks to be a very good option for type 1 diabetes. The SGLT2 inhibitors have been tested in type 1 diabetes and there are a couple findings. One is that when it comes down it reduces some of the very high blood sugars that occur after meals. Patients feel quite good on them. So what are the problems with that class of drugs? They have an off target effect of producing ketones. Well ketones are sort of the enemy in type 1 diabetes. And if ketones get too high it may produce a serious problem called ketone acidosis. So in the SGLT2 studies there is a higher rate of diabetic ketone acidosis. And it’s a very serious problem may require admission to hospital maybe even to an ICU. In the end it’s something we avoid. We take great lengths to avoid DKA. There is a little higher rate of DKA in patients taking the SGLT2 inhibitors. So how do we manage this? We do a couple of things. There are meters available for checking ketones. You can actually check your ketones and learn whether your ketone levels go up. We really counsel patients about the risks. Nonetheless in the clinical trials there was an increased rate. And that increased rate of ketones acidosis caused the first one, called sotaclofosin. So sotaclofosin was presented to the FDA after a couple of large clinical trials in type 1 diabetes. And the advisory committees split. And it split in an interesting way. The endocrinologists wanted to see it approved. And those who were more risk averse voted against it. So the FDA declined to approve sotoclofosin for use in type 1 diabetes. It’s currently being tested for type 2 diabetes. The others have not gotten that far with FDA approvals or submissions.
There are four others. So we don’t know the outcome of what the FDA will say about the others.
Using it off label isn’t always easy because sometimes insurance won’t cover it. Could the fact that the FDA did not approve this for type 1 hurt our ability to get it off label? Will that hurt type one’s access to it?
MCGILL: Doctors prescribe drugs off label often. And we have to because drugs are not tested in every situation in which they may be appropriate. That being said these are expensive drugs and access is limited and variable. So it becomes rather confusing. We don’t always know in advance if it will be approved.
They are expensive if the insurance didn’t approve it. They are five or six hundred dollars a month kind of drugs. Right?
MCGILL: They’re expensive.
They’re expensive. So we really need to have these be approved for type 1.
MCGILL: Endocrinologists should hope to see one or more of these approved. There are other reasons we’d like to see them approved. In studies of patients with type 2 diabetes they’ve been shown to have both cardiovascular and renal benefits. And we would like those benefits to be available to our type 1 patients. Those benefits are now so clear that we would like to use the drugs in those patients.
Also one of the benefits is an amazing side effect is that you lose some weight on this. Isn’t that true?
MCGILL: Weight loss is modest. We still need therapies that help with significant weight loss. But it does prevent you from gaining weight because of needing to snack when your blood sugars are low and all kinds of other insulin driven problems. So it does help prevent weight gain which is just aggravating. And it does prompt a little bit of weight loss partly by reducing your insulin requirements by a small amount. But it’s enough.
Does the DKA present the same on these drugs?
MCGILL: Well DKA has a variable presentation. Some of it comes on very quickly. Others it takes several days. And then it appears to be there. Some patients recognize it and can do all the right things and avoid having it progress. Others are in the hospital very sick. So it’s difficult to say that it’s particularly different. It fits within kind of a usual DKA presentation. And we try to inform patients and educate them about these risks. The problem is most adults do not have DKA very often feels like they’ve got the flu. So they’re not ready for it. And it they don’t know what it feels like. And so it’s a little sneaky in someone who hasn’t had DKA for 20 years.
It can present with the normal blood sugars though for this on drug right?
MCGILL: DKA is softly defined as a blood sugar less than two hundred and fifty. That’s still not normal. It’s lower than six and seven hundred. But we still see very high blood sugar presentations. So it can be a little bit lower and in type 2 sometimes it’s lower. It’s not normal blood sugars. Usually they’re not normal. But they’re below the threshold where you think about DKA.
What is the benefit for type ones to have? How is having something other than insulin for Type 1 offer those patients?
MCGILL: Hazardous insulin can cause hypoglycemia and can cause weight gain. Giving insulin is difficult. And it’s hazardous. So anything we can do to just offset the reliance on insulin. We often see a benefit for patients whose A1Cs were never great.
END OF INTERVIEW
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