Importance of Postprandial Glucose Control

CARLOS R. HAMILTON, JR., MD, FACE: Hello. I'm Dr. Carlos Hamilton and welcome to the AACE Clinical Conversations. In this program, we will discuss the importance of postprandial glucose control. Joining me in our studio to discuss this topic is Dr. Eric Orzeck, Clinical Associate Professor in the Department of Internal Medicine at Baylor College of Medicine. Joining us by telephone is Dr. Philip Levy, Clinical Professor of Medicine at the University of Arizona College of Medicine. Welcome, Phil and Eric, and thank you both for participating in this program.

ERIC A. ORZECK, MD, FACE, CDE: Thank you.

PHILIP LEVY, MD, FACE: Thank you for asking us.

CARLOS R. HAMILTON, JR., MD, FACE: We all know that blood glucose control is a very important thing for our patients with diabetes. Philip, tell us a little bit about some of the new guidelines and current recommendations for fasting blood and postprandial glucose levels.

PHILIP LEVY, MD, FACE: Well, the American College of Endocrinology and the American Association of Clinical Endocrinologists has set up some guidelines for control and those guidelines include obtaining a hemoglobin A1c value of 6.5% or less. We've also set postprandial guidelines of 140 mg percent with fasting guidelines of approximately 110 mg percent.

Basically, we're trying to get these numbers as close to normal as possible because of the vast amount of evidence indicating that the closer we get to normal, the much better we do in terms of both microvascular complications and macrovascular complications.

CARLOS R. HAMILTON, JR., MD, FACE: Well, thank you very much. Now, Eric, when we're monitoring our patients' glucose levels, which values are the most important, the postprandial, the fasting, the bedtime blood sugars or the hemoglobin A1c?

ERIC A. ORZECK, MD, FACE, CDE: They're all important. All of them react to a different area of management. The fasting glucose is usually higher in the morning whether somebody has diabetes or doesn't because of what's called the dawn phenomenon. We need to get that under control. We need to treat for that as well as making sure that the bedtime glucose is not so low that there might be some problem with hypoglycemia overnight and into the early morning hours, which can paradoxically raise the fasting blood sugar, so it's important to know what that value is to be able to determine if the elevation is due to poor control in that there is too little in the way of treatment or too much in the way of treatment with a rebound.

And the postprandial values are the values that drive the hemoglobin A1c levels so that they're even more important than we originally recognized as far as the overall management in the patient with diabetes, so all of them play a role.

CARLOS R. HAMILTON, JR., MD, FACE: I think you may have answered this question in part, but how does the postprandial glucose level relate to the overall glycemic control as indicated by the hemoglobin A1c?

ERIC A. ORZECK, MD, FACE, CDE: As the hemoglobin A1c values to the normal range or to the range that Dr. Levy mentioned as far as a 6.5% or less, the postprandial glucose plays a significant role, probably 75 or 80% of the glycosylated hemoglobin, hemoglobin A1c under 7% is related to the postprandial values that are not well-controlled. If they are not well-controlled, the values of the A1c will rise.

CARLOS R. HAMILTON, JR., MD, FACE: So if a person has a reasonably normal fasting blood sugar and their hemoglobin A1c is still high, then you can count on the reason for their hemoglobin A1c being high is because their postprandial glucose is not as well-controlled as it needs to be.

ERIC A. ORZECK, MD, FACE, CDE: That is absolutely correct. The postprandial values will play a major role in what the hemoglobin A1c is and if the patients are just testing fasting or at bedtime and aren't monitoring two-hour postprandial glucose levels, that contributor to the hemoglobin A1c is going to be missed.

CARLOS R. HAMILTON, JR., MD, FACE: Philip, is the postprandial glucose control an independent factor in the outcomes of our diabetic patients?

PHILIP LEVY, MD, FACE: Yes, it certainly is, Carlos. We have a lot of evidence, for example, that just modest elevations of postprandial glucose with normal fasting glucoses are associated with increased mortality and also increased cardiovascular morbidity. There are a number of studies that have shown this, perhaps the largest of which is the DECODE study, which was done in Europe. But also, in addition, there are studies like the Honolulu Heart Study, where an IV glucose challenge was given and, generally, in these studies, the higher the postprandial glucose is, the more likely we would have mortality and also cardiovascular morbidity. So it seems like it's important to control these.

What we don't have yet is we don't have large epidemiologic studies to show that controlling the glucose alone will make a difference in these outcomes and those studies, however, are pending, but we do know that, if the glucose is up, people are at increased risk. And, of course, in these people who have just postprandial glucose elevations, we also stress the importance of treating any concomitant comorbidities like hypertension and dyslipidemia.

CARLOS R. HAMILTON, JR., MD, FACE: Well, Phil, we all know that, when we're treating patients, we're not just treating a blood sugar level and, in order to really manage diabetics, you have to be just as aware of their blood pressure and their lipid levels as you are of their blood sugar and that is certainly a fact that we don't want to not emphasize appropriately.

But, Eric, let me ask you something. What are the effects of postprandial glucose control on these cardiovascular complications, both the macrovascular and the microvascular?

ERIC A. ORZECK, MD, FACE, CDE: We are very fortunate in having two studies come to publication, the DCCT, the Diabetes Control and Complications Trial. In the mid-'90s, was a type 1 study of exactly what the name indicates, how does the management of diabetes relate to complications. And the UKPDS or the United Kingdom Prospective Diabetes Study is a study that was in type 2 patients and both studies clearly, clearly showed that the higher the A1c, the more severe the complications and that just minimal lowering (meaning a 1 percentage point drop in the A1c) can have a profound improvement in patients with retinopathy and nephropathy, along with the macrovascular, cardiovascular disease.

CARLOS R. HAMILTON, JR., MD, FACE: Well, this is really important, because not only are the usually appreciated complications of diabetes, including the retinal changes, the kidney changes, these are the microvascular changes, but the macrovascular changes are equally affected by this and those are the ones that cause the loss of limbs and the myocardial infarctions and stroke and so forth.

ERIC A. ORZECK, MD, FACE, CDE: Exactly.

CARLOS R. HAMILTON, JR., MD, FACE: Philip, let me ask you again, you know, we're talking about diabetic patients. Most of our patients are older patients, but there are a fair number of young women, especially those that are pregnant, for whom blood sugar control is extremely important. Is the postprandial glucose level critically important in the management of these patients?

PHILIP LEVY, MD, FACE: Yes, absolutely. I think there's abundant evidence that controlling postprandial glucose in, for example, gestational diabetes or even with overt diabetes is very important in terms of reducing the complication rate in pregnancy and bringing about normal -- normal pregnancy results, probably more so in pregnancy than anywhere else in terms of this having been shown and proven over and over again.

CARLOS R. HAMILTON, JR., MD, FACE: Eric, tell me a little bit about some of the current methods and some of the ways that you try to control postprandial hyperglycemia in your patients.

ERIC A. ORZECK, MD, FACE, CDE: We have many different medications and programs available. Starting perhaps in the order of their availability, we've had the alpha-glucosidase inhibitors such as Glyset and Precose, which act in the intestine to delay carbohydrate absorption. We have the meglitinides such as Prandin and Starlix, which work on the beta cell to improve insulin response to hypoglycemia. And we have had a new entrant into the rapid-acting insulin armamentarium of Humalog, NovoLog and now Apidra and these are insulins that mimic the insulin production in someone without diabetes as far as absorption and, therefore, handling the glucose load.

In addition, now, we have the incretins, which are medications which mimic the amount of GLP-1 in the system which are injectables, Byetta and Symlin, and both of those are designed to decrease the amount of glucose absorption by delaying gastric emptying, by stopping the liver from making glucose inappropriately and also secondarily improving satiety.

In addition, just recently, we have a medication called Januvia which blocks DPP4. DPP4 is what cleaves GLP-1, so if we can block it from getting rid of the GLP-1, we can improve the natural state of the medication to do what Symlin and Byetta are doing as well.

CARLOS R. HAMILTON, JR., MD, FACE: Of course, in addition to these new drugs, another method for controlling postprandial hyperglycemia is to advise your patients not to eat so much, perhaps, or perhaps to go easy on the desserts. And, unfortunately, that sometimes is not always an easy thing to do.

But we do have a lot of new drugs and new methods and techniques available for controlling this thing. Philip, tell us a little bit about some of these newer diabetic drugs such as the amylin derivative of pramlintide and the GLP-1 synthetic peptide exenatide. How do these work and how should they be used?

PHILIP LEVY, MD, FACE: Well, pramlintide actually is a derivative of amylin. Amylin, the beta cells of the pancreas make two hormones, they make insulin and they also make amylin. So, in somebody with longstanding diabetes, amylin is insufficient and pramlintide is really replacement of amylin.

And, basically, as Eric mentioned, amylin has almost the same actions as exenatide, which is a GLP-1 mimetic and let me just briefly explain that GLP-1 is what we call an incretin. Incretion comes originally from the words "intestinal secretion of insulin" and what happens is, when we eat something by mouth, rather than, let's say, take it IV, there are some hormones that are produced by the small intestine and GLP-1 is probably the most important of these and it comes from some cells in the small intestine called the L-cells, which are mostly in the distal small intestine, although, to some extent, they're more proximal as well.

The GLP-1 normally is secreted in response to a glucose load, so if we eat a meal, GLP-1 comes out and what GLP-1 does is it increases the insulin response to a glucose load and it also cuts back on the alpha cells making glucagon and, as you know, glucagon produces increased glucose production by the liver, so that we have a nice compensatory mechanism. When we eat, we don't need glucagon, so that goes down. We do need insulin and so GLP-1 stimulates insulin production.

In the diabetic, unfortunately, GLP-1 is deficient and glucagon is hyperproduced in response to the glucose load. So we have too much glucagon and we obviously don't have enough insulin. So these drugs that are GLP-1 mimetics (and the one that we have on the market now is exenatide or Byetta) basically bring back the normal GLP-1 response and they help control diabetes in that way.

CARLOS R. HAMILTON, JR., MD, FACE: All right. Eric, we obviously have a lot of agents and drugs and things that we can do. Tell us a little bit about how you approach patients with elevated postprandial blood sugar levels and how you advise them and how you go about managing this problem.

ERIC A. ORZECK, MD, FACE, CDE: Clearly, everything that has been mentioned, including your observation of the need to make certain that dietary management is closely followed along with exercise, events that we too often just either ignore or don't put enough weight to the patient. And I think the patients would do better if we were to mention these to them on a more regular basis and to stress the need for them.

But, we do have the ability to tailor our treatment programs in regards to medications. Some patients can do well with the blocking of the carbohydrate absorption. Others can do well to have the insulin production in the pancreas improved with the meglitinides, Prandin and Starlix. And others are going to need not only insulin, perhaps, but also the addition of one of the incretins to cover the other parts of the management team, so to speak, that isn't covered by these other medications, such as the the liver directly not putting out as much glucose and also having the individual feel fuller sooner so that they don't overeat, just from the fact that the food's available to them.

CARLOS R. HAMILTON, JR., MD, FACE: So we start off with dietary management and, in situations where this is not enough, then we can use some oral medications like the ones you mentioned to help increase insulin production. Giving insulin prior to meals is another alternative, especially the short-acting insulin and then we have these newer agents that can be given by injection prior to a meal that help deal with some of these other problems that you and Phil have already described.

ERIC A. ORZECK, MD, FACE, CDE: And they're much more physiologic because they cover more than just insulin deficiency by the injection. As Phil mentioned, it covers all of the parameters that, if the body doesn't have the GLP-1, for instance, it's not going to get the coverage for these other problems.

CARLOS R. HAMILTON, JR., MD, FACE: Phil, do you have anything else about the way you manage your patients that you wanted to tell us?

PHILIP LEVY, MD, FACE: No, I don't think so, Carlos. You know, what's interesting now is we have so many options that we didn't have before and probably the most common decision is gonna be when you have somebody that you've been treating, let's say, with combination therapy with two oral agents addressing the pathophysiology of diabetes; that is, insulin resistance and decreased beta cell production. We used to have very little in the way of alternatives once that happens.

Now we have a lot of alternatives, which I think Eric has very nicely outlined, and I think we're very fortunate in having all these treatment options and I think the introduction of the whole incretin family, the incretin mimetics and, you know, now the DPP4 inhibitors, I think, is gonna offer us much more for our patients.

CARLOS R. HAMILTON, JR., MD, FACE: Well, thank you very much, Phil. We really do have a lot of new agents and new things that we can do to help our patients. I believe that's all the time that we have. I think this has been a very good discussion on the importance of postprandial glucose control. I'd like to thank Dr. Philip Levy for joining us by phone and thank you, Eric, for joining us here in the studio.

I'm Dr. Carlos Hamilton and thank you all for watching.