← Diabetes Core Update
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- [00:03]
A
Welcome to the special series of Diabetes Core Update where we will discuss continuous ketone monitoring in people with diabetes. Yes, I said continuous ketone monitoring, not continuous glucose monitoring. We're going to discuss a new technology today that stands to improve the care of people with diabetes and is currently being evaluated under expedited review at the fda. While we speak now, you might be thinking, why is ketone monitoring important? Well, we're going to answer that question today. I'm your host, Dr. Neal Skolnick, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. This special series of Diabetes Core Update is sponsored by by Abbott. And joining us to discuss this topic is Dr. Guillermo omperes. Dr. Imperis is a professor of medicine in the Division of Endocrinology and Clinical director of the Diabetes and Metabolism center at Emory University School of Medicine and Director of the Diabetes and Endocrinology Section and Clinical Research Unit at Grady Memorial Hospital in Atlanta, Georgia. Guillermo, I have wonderful memor of Grady Hospital because I went to medical school at Emory and it is just one of the largest, most caring city hospitals that I've ever seen or heard of. In addition, Dr. Imperis is the recipient of numerous national awards from the American College of Physicians, the American Academy of Clinical Endocrinology and of course the American Diabetes Association. He is a member of the ACE Diabetes Scientific Council and Board of Directors of ace. He is chair of the Global Task Force and member of the ADA Professional Practice Recommendation Committee. And relevant to today's discussion was chair of the ADA Consensus Report on Hyperglycemic Crises in Adults with Diabetes. Welcome Guillermo.
- [02:22]
B
Thank you so much for having me today. It's a pleasure and I'm so glad that you trained at Grady.
- [02:28]
A
It was, it was one of the most amazing experiences. It's big, it's filled with energy and it is filled with really caring people. Thank you Guillermo. Why should we care about continuous ketone monitoring?
- [02:45]
B
Well, continuous ketone monitoring or CKM as we call it now is allows real time tracking of blood glucose levels and ketones levels. It help if you monitor ketones levels early on. It help you to detect the risk of diabetic ketoacidosis and prevent severe dka. The DKA is the number one reason or mortality cause in adolescents and young adults. So in patients with type 1 diabetes and those who are at risk of developing DKA would be very helpful. So who are those patients with type 1 diabetes who has poor control patients with type 1 diabetes during pregnancy, those who are taking SGLT2 that will apply not only in Taiwan, but also in patients with type 2. So we are waiting, and I think that this is going to be very, very helpful for the management of patients with diabetes.
- [03:48]
A
Yeah, and I think you're right. And a lot of our listeners are no longer managing inpatient care. We do in our practice. And it just seemed for a while we weren't seeing a lot of dka. And then over the last few years, it seems like we're seeing more. Is that consistent with the. The data out there? Has there been an increased prevalence for some reason of dka?
- [04:12]
B
Right now in the United States, we have somewhere around 225,000 patients with diabetic ketoacidosis every year admitted to the hospital, and many are not admitted to the hospital. So during the past few years, despite all the advances in monitoring and treatment, we still have numbers that are absolutely unacceptable. So having tools to identify and to treat and perhaps prevent those patients with diabetic ketoacidosis are going to be very useful. This is all over the world, not only the United States, but the same thing in Europe. The number of diabetic ketoacidosis has increased in the last few years.
- [04:54]
A
Interesting. Now, since many of our listeners aren't still taking care of dka, let's just go back for a second and can you remind us of the pathophysiology of DKA and you tell us a little bit about its consequences in terms of mortality? Pathophys?
- [05:13]
B
Yeah. It is more common in type 1, but it may happen also in type 2. And the consequence is lack of insulin secretion or increased insulin resistance in peripheral tissues. But the number one reason is low insulin levels. And everybody has very low insulin levels. And when you cannot use glucose because there is no insulin, to put glucose inside the cells, you need alternative fuels. And that alternative fuel for metabolisms are ketones. So what the body does is break down triglycerides. You get free fatty acids. Who goes to the liver. While compared to ketones, they are acetoacetane and beta hydroxybutyrate. So why? It's just because the body needs. And that's where we get diabetic ketoacidosis. Sometimes in patients during acute infection, in type 2, mostly in type 1, but also in type 2 infections or acute myocardial infarction, you increase catecholamines and other contra regulatory hormones that counteract the action of insulin and may develop diabetic ketoacidosis.
- [06:23]
A
And so when someone has obviously an infection we're going to see manifestations of the infection clinically. What are the clinical signs and symptoms of DKA that people begin to have?
- [06:36]
B
So if you don't have insulin, your blood glucose goes high. The average blood glucose in adults with DKA is about 600 to 700. So that results in polyuria and polydipsia. And of course that increases thirst. With increased acidosis, the patients are going to have nausea and vomiting. So anybody who had blood glucose greater than 2 and 300 in the presence of gastrointestinal symptoms like nausea, vomiting and many times with abdominal pains are the classic symptoms. If the DKA progress, they develop other mental status, even coma.
- [07:23]
A
And for a patient who has type one, what do we suggest that they ought to look for? If we're advising them about early detection, is there a way they can tell?
- [07:34]
B
Yeah, the hallmark is both. Diabetic ketoacidosis is diagnosed with three legs, one is the presence of hyperglycemia. But now we see patients that for example type 2 diabetes who are taking SGLT2 who may present with diabetic ketoacidosis with levels less than 200, 250, or a patient who has mildly treated may present with diabetic ketoacidosis but not severe hyperglycemia. That is the reason why in the new guidelines we diagn, we suggest a blood glucose greater than 200 and a history of diabetes. It doesn't matter what glucose you have. If you have elevated beta hydroxybutyrate or ketone, that's number two, like levels of beta hydroxybutyrate greater than 3 mil of mole, or they are doing urine test more than 2 plus that will qualify for diabetic ketoacidosis. And the third ketones bodies are strong acids and need to be buffer and be buffer with bicarbonate. So that would patient present with metabolic acidosis, usually high annual gut metabolic acidosis and of course low ph. So high high ketones, metabolic acid.
- [08:55]
A
And when we talk about ketone bodies, there are two major ketone bodies, right? And one is what we're detecting on the regular old urine dipstick, the other what we measure in blood. Can you tease that out for us a little bit?
- [09:11]
B
Yeah. And you may like this. PKANS has been measured since the 19th century. In the 1890s, they already laboratory measurements in the urine test acetoacetate and at that time they didn't know what DKA was, but they knew that they compensated a diabetic common presenter with acetoacetate. In New York and now in that, that progress in the 1900s and 1950s to have these sticks, and that's what most people has managed. And the determination of ketones levels we can also measure in the laboratory by enzymatic tests. But in somewhere around 20 years ago we start having some strips to do point of curve testing. They are widely used in Europe, not very much in the United States. So the best thing when somebody have nausea or vomiting, you have a history of diabetes, you have polyuria, polydipsia, you don't feel well, you have abdominal discomfort, is to first check blood glucose levels. But most importantly, the hallmark is level increased concentrations of beta hydroxybutyrate. The sensitivity of acetoacet A by dipstick is very good, 90 plus percent.
- [10:27]
A
Hmm.
- [10:28]
B
But the accuracy is not very good. So that's why we would like most people to measure beta hydroxybutyrate. Unfortunately, most hospitals do not measure. In the United States, half of the hospital is still relating on acetoacetate for diagnosis of diabetic ketoacidosis. And this unfortunately, because we have tools now to measure by the laboratory and hopefully in the future, with the continuous meters, we can detect early on and prevent admission to the hospital and likely prevent readmissions.
- [11:02]
A
So let's move to that early detection idea. Is there a period of time for people who are going into DKA that there are measurable amounts of ketones? You know, I would imagine someone starts feeling not well long before they have full blown DKA is there that period of time during which you can begin to see beta hydroxybutyrate rise where an intervention, a simple intervention might be helpful.
- [11:35]
B
That's excellent point. What is normal dexybutyrate? Well, a level less than 0506 millimole normal in acetoacetate in the urine, it should be negative. So if you have levels above.06 to 1.5, this is like yellow car. And from 1.5 to 3, you are impending. Diabetic ketoacidosis in the new guideline would suggest that levels more than 3 millimole, that's defined as diabetic ketoacidosis. And the reason is that levels more than 3 correlate with the severe metabolic acidosis. So that's what we'd like to do and, and not everybody just with diabetic ketoacidosis develop high ketones. For example, who else can have high ketones? For example, those who are doing starvation ketosis or missing meals. A patient with type 1 diabetes on a very low calorie Diet may develop diabetic ketoacidosis. So if they are doing the ketones, that low calorie diet, they can look at what levels of ketones they have and prevent progression. Many patients do not have symptoms, especially for example those who have taken SGLT2 inhibitors. They don't have even many of them, 20% of them don't have hyperglycemia. So severe hyperglycemia, the glucose in there 100, 200. So those kind of patients are silent Diabetic ketoacidosis. Having a tool to recognize elevated ketones levels may be extremely useful.
- [13:19]
A
That's interesting. So let's say we have a patient who has type one and they're monitoring their ketones and they see a rise from that under 0.52. Now it comes back at 1. What would they do? What's the intervention that early detection leads to?
- [13:42]
B
Yeah, and I would answer this in two in two ways. One is patient with insulin pumps. That's right. And in the past we said insulin pump were associated with increased risk of dka. Now that risk is very very minor. However, sometime they have malfunction and the first thing they do is to have elevated glucose. But many patients have even ketones levels elevation before they have high blood glucose. So in those patients early recognition that they're going into diabetic ketoacidosis, they check the pump, they check if they're receiving insulin or not daily, the tubing is quick or stop. So early on you can. Those patients were treated with SGLT2 for example, who has had a previous history of DKA or poorly controlled diabetes they can have early on. So all patients who are poorly controlled. Right. What would they do or what they should. So first hydration, look at the glucose concentration, make sure they are getting insulin. And now we have several algorithm how you should manage patient with early diabetic ketoacid. Those even you know, low doses of insulin every one or two hours with increased hydration with some carbohydrate in the beverages. So and we have I'm, I'm running a clinic where we see 80 patients a day and many patients come with blood glucose of 500, 600. Some mild ketones, we manage them with 0.1 or 0.05 units per kilo every hour. And we monitor and make sure they resolve before they are admitted to the hospital. Cognition is the key to prevent safe diabetic ketoacidosis, hospital admission, ICU admissions.
- [15:35]
A
It is so helpful how you segmented it out because one is just clearly A technology malfunction alerts you, you take care of it. The other could be a range of things from the reality is many people just for whatever reason might not be taking their insulin. This is an extra, you know, alert that you better be on it or the amount of insulin is insufficient. So it's clear that early detection leads to an action that can make a difference. Can you tell us a bit about the devices that are in development and particularly the device at the fda? How do you see it being used in practice?
- [16:14]
B
Yep. And. And we have had continuous glucose monitoring now for several decades. In the last few years they are pretty accurate and have helped significantly in the management of patients with type 1 and type 2 diabetes. They're even now recommended for everybody with type 2 on insulin therapy, glucose is good, but in diabetic ketoacidosis and many times people develop high ketones, but you don't know what the glucose levels are and don't even correlate all the time. Having ketones, congenial ketone is going to be, is very helpful. And now if we have a dual glucose ketones meters that is in the same device, the same needle, the same injection process that you can have in the same device, measuring blood glucose and ketones at the same time is going to be extremely helpful. So you don't have to just request ketone. It's just going to tell you the current technology evaluated by the fda. We hope to hear from them in the next few weeks, months, and if it's approved, it's going to become extremely helpful for managing patients with type 1 and certain patients with type 2 diabetes.
- [17:37]
A
And so this is both in the same device and it's measuring the ketone part is measuring data, Hydroxybutyrate. Right. Not acetone. So it's accurate, it can give you a sense of level. So one could then know what level of intervention is needed. Do you need to get over to the ER quick or do you have interventions that can be done as an outpatient? One of the things that's always challenging for people is the just the amount of things. You have to pay attention to the number of different devices. It sounds like this is not going to make things a lot more complicated because it's in the same device and goes to the same reader, is that correct?
- [18:20]
B
Yeah, you're right. And it's going to measure every minute, but you get the information for both glucose and ketones every five minutes, 24, 7 and it will have alarms. So it is my understanding that when it comes to the Market or is this approved by the FDA is going to let you know if you are below 0.6, below 1.5 or more than 3 if you have more than 3. I don't think it much makes much difference to me if you are 3, 4, 5. The other beta hydroxybutyrate in patients with diabetic ketoacidosis is about 6 to 8 millivolt. But if you have more than three, it's associated with acid based disorder. So more than three, you get diabetic ketoacidosis. And can you imagine that if you have a patient with the glucose going from 100, 200, 300, the patient is in an insulin pump despite your push getting you more insulin. The next thing would be look at your kidrons because matter of just a few hours it's going to be extremely helpful to determine that hyperglycemia likely is due to pump failure or you have somebody who has a bad cold, you have type 1, your blood glucose go up to 2 and 300. Right now if you ask patients with type 1 diabetes, do you ever check ketones? No. Very few of them. When you are young, your mom does it for you. When you're adult, more than 30 very few patients with type 1 are currently tested. Why? Because it's not really available, it's expensive and urine testing is kind of messy. That's right.
- [20:03]
A
So, so there's the less than 0.5 is normal above 3 is, is worrisome. Does it let you know in between there where you are at if you're in that middle zone above normal but not full blown dk.
- [20:17]
B
That's right. So it's an alert and if you have levels of between more than 1.5 that means do something or call your physicians or start getting protocols. How are you going to test for insulin infusion? Start getting more insulin injections, start hydrating yourself and look at the blood glucose and of course look at the ketones levels because the levels less than 0.6 correlate with resolution of diabetic ketoacidosis.
- [20:48]
A
That's helpful. So with any new technology we usually don't roll it out to everybody. We decide which patients we're going to in essence start using it on first. Who would you recommend as the high risk groups that ought to be having this technology as soon as it comes out?
- [21:10]
B
Yeah, so patients with type 1 diabetes, patients who, I mean they can get the glucose and ketones levels, especially those who are not very well controlled. Patients who had a previous history of admission to the Hospital with hyperglycemia or TKA patients who are even those patients with type 2 who have been on SGLT2 and have decayed in the past. That could be a way to prevent. Hmm. But I think for everybody who has type 1 diabetes it may be a good thing to do. So the other thing is that pregnancy so patient with type 1 diabetes, even type 2, but especially type 1 during pregnancy have an increased risk of diabetic ketoacidosis. You remember that the insulin resistance is in everybody who is pregnant because you have this placenta producing contra regulatory hormones. So in those patients and during pregnancy levels of beta hydroxybutyrate are higher than non pregnant patients. And there's a lot of questions how bad it is to have high ketones levels. So I think that that for sure patients with type 1 should be offered. You want to get a CGM or would you want to get a dual CGM and and look at ketones the and some others with type 2 would be less. The final that I believe is going to happen is that those patients who are for weight loss, who are glycemic control, follow the very low calorie diet, develop ketosis, they have levels of 2, 3 and even more if they don't eat for 24 hours. And if you eat less than 800, 400 calories a day because you're in those very special times that you can follow. We recently published a paper that if you're following a very low calorie diet, taking an SGLT2, you have an increased risk of decay. So those are the kind of patients that perhaps we're going to be using. But of course once we gets in our hands now, we're going to have several studies that are going to define really who really benefit. But I will say Taiwan, this is
- [23:26]
A
really helpful and we're going to follow up in a future episode with some cases where we'll go over examples of people who fit the ideal for using this and what to do with some of the information that comes back. We're about out of time. This is such an exciting area of new technology and new technology we know just moves a lot quicker now than it used to in terms of from new to routine use. We're about out of time. Any final thoughts Guillermo, that you might have for our listeners?
- [24:02]
B
Well, thank you so much for having me today and I agree with you. This is a new technology. We went from testing urine for glucose. Now we now have moved to finger sticks. Now we have continuous glucose monitoring and in parallel, unfortunately, we had had urine ketones, that very few are using blood ketones. And now we're going to have have continuous ketones. And I hope we're going to have continuous glucose ketones who are going to be extremely helpful to early diagnosis, prevention, prevention of TKA and management of patients. 1/3 30% of patients with diabetic ketoacidosis are readmitted within 90 days. Can you imagine if you have something that may prevent a tool that readmission? So I'm looking forward new technology, new life. For a lot of people with type one, of course, for those of us who do research, can't wait to have it.
- [25:07]
A
This is really exciting. And that statistic about the readmission rate is startling. It's scary. And clearly a group of people that will benefit enormously from this. Dr. Guillermo and Perez, thank you so much for joining us.
- [25:24]
B
Thank you.
- [25:25]
A
And most of all, as always, thanks to our listeners. Thank you for joining us on this special edition of Diabetes Core Update, discussing integrated dual continuous glucose and ketone monitoring in people with diabetes, an exciting technology that is soon going to go from a hope for the future to our reality that we can prescribe. This special edition of Diabetes Core Update is sponsored by Abbott. We thank you for listening. For the American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning. Sam.