Glycemic Control in Type 2 Diabetes Mellitus: Initial Treatment

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 glycemic control in type 2 diabetes mellitus and review options for the initial treatment of the disease.

Joining me today is Dr. Alan Garber, Professor of Medicine and Professor of Biochemistry and Molecular Biology, Professor of Molecular and Cellular Biology at the Baylor College of Medicine. He is also on the Board of Directors of the American Association of Clinical Endocrinologists.

Dr. Glenn Cunningham, a Professor of Medicine at Baylor is also with us. He is a professor also of Molecular and Cellular Biology at Baylor, and the Medical Director of the St. Luke's Hospital, Baylor College of Medicine diabetes program. Thank you Glenn for being with us.

We all know that one of the big problems in diabetics has to do with diet and exercise, and we've all been taught that that's what we need to teach them initially. What do you generally tell new patients with diabetes that come to you, whether they are newly diagnosed diabetics or whether they've had the disease for a while? What kind of advice do you give them?

GLENN CUNNINGHAM, MD: I always try to stress the importance of diet, and if they are overweight, which most of these patients are, then I talk with them about weight reduction as well.

Usually, I try to get them to see a dietitian to see if she can identify ways that they may be able to reduce their total caloric intake.

In terms of exercise, I think that's extremely important. I think it's very difficult to get people to maintain their weight loss without some kind of an exercise program.

In the case of individuals who are really going to become involved with a serious exercise program, then I frequently ask them to go ahead and do cardiac stress testing before they initiate that.

CARLOS R. HAMILTON, JR., MD, FACE: Yes. Alan, what do you generally tell people, and what kind of success do you have with this sort of advice?

ALAN GARBER, MD, PhD, FACE: The most common failing that I find in patients with diabetes is the underestimation of portion sizes. And diabetes educators are very good at reinforcing the fact that when it says three ounces of meat for lunch, that's really a microscopic portion, much less than people are used to picking out. But that's really all that's on the menu.

And so you have to then reeducate people about these portion sizes that have grown so large that everyone expects to take home great sacks of food from every restaurant they go to.

CARLOS R. HAMILTON, JR., MD, FACE: Well, there is no question but that diet and exercise are important. And we always teach our patients. I personally have found that professional diabetes educators, who are in part dietitians as well as diabetic educators, do have some success, mainly because they're usually very enthusiastic people that stimulate people's interest in trying to participate in the program. But unfortunately, not everyone has access to that or is willing to do go that extra mile.

So there are obviously a lot of patients with type 2 diabetes for whom exercise and diet management is simply not enough. It is those patients that we want to talk about, I think, today.

Glenn, what is your first approach to them from a standpoint of medications?

GLENN CUNNINGHAM, MD: Normally, I would start with metformin, unless they have enough renal impairment that makes it unlikely that they should be treated that way. If that is not sufficient, then we have to move on. But I usually start them at a lower dose, work my way up, try to avoid GI side effects and then see what effect that has on control.

CARLOS R. HAMILTON, JR., MD, FACE: You mentioned renal impairment as a problem with metformin. How much of a problem is this and what degree of renal insufficiency makes you absolutely not want to use this modality?

GLENN CUNNINGHAM, MD: Normally, I will not use it in women if their serum creatinine is 1.4 or in a man if their serum creatinine is 1.5.

CARLOS R. HAMILTON, JR., MD, FACE: And that would equate, of course depending on their age and other factors, a glomerular filtration rate of in the less than say, 50 or 60...

GLENN CUNNINGHAM, MD: Probably less than 50.

CARLOS R. HAMILTON, JR., MD, FACE: Have you actually seen problems with it in patients at that level?

GLENN CUNNINGHAM, MD: My experience has been that there are very few patients who develop metabolic acidosis because of this drug. I think it's very rare. But probably in part, that's due to the fact that we're cautious in using the drug.

CARLOS R. HAMILTON, JR., MD, FACE: Well, I think to some extent, we may be so cautious...

GLENN CUNNINGHAM, MD: Over cautious, yes.

CARLOS R. HAMILTON, JR., MD, FACE: ...there are a lot of people that would benefit from it that don't get it.

GLENN CUNNINGHAM, MD: I agree with that.

CARLOS R. HAMILTON, JR., MD, FACE: Alan, what is your next step, assuming you would also start with metformin?

ALAN GARBER, MD, PhD, FACE: Either metformin or a thiazolidinedione. There is a recent large-scale clinical trial of three different classes of oral agent, ADOPT, published in the New England Journal in December, which looked at initial therapy with sulfonylureas, metformin, and a thiazolidinedione, in this case rosiglitazone, and showed much more durable control with a thiazolidinedione with about a 60 month life span of A1cs below 7% before this deteriorated, whereas metformin had a 45 month life span and sulfonylureas much less, 33 months.

One would therefore be inclined to favor the more successful drugs that produce more durable glucose control, metformin and particularly thiazolidinediones, over agents that have evanescent control that you can expect to have difficulty in the near-term in terms of the need for more and more agents.

CARLOS R. HAMILTON, JR., MD, FACE: Now excuse me. This particular study used these as a single drug over this period of time.

ALAN GARBER, MD, PhD, FACE: Yes.

CARLOS R. HAMILTON, JR., MD, FACE: And they were able to get a significant number of their patient's hemoglobin-A1cs to 7 or less.

ALAN GARBER, MD, PhD, FACE: Correct.

CARLOS R. HAMILTON, JR., MD, FACE: That's remarkable in my practice. I have very few patients who do that. Glenn, what is your...

GLENN CUNNINGHAM, MD: Well, I think these were relatively new onset, newly diagnosed type 2 diabetics, so it's feasible in that setting to start with monotherapy. But I agree with you. In patients who have longer-standing disease, most of the time you have to use combination therapy.

CARLOS R. HAMILTON, JR., MD, FACE: Alan, what is your combination therapy that you go to if one of these doesn't work?

ALAN GARBER, MD, PhD, FACE: Well, having published a number of studies with combination therapies, right at the moment, the one I'm sort of recommending is a metformin/thiazolidinedione combination of Avandamet, which we recently showed was able to produce a 2.3% reduction in A1cs with no weight gain.

That to me is a very nice combination of efficacy without disturbing the kinds of diet and exercise recommendations that Dr. Cunningham and I have already suggested are good things.

CARLOS R. HAMILTON, JR., MD, FACE: And the thiazolidines, do you start off with a low dose and build up over a period of time, or do you think that's important?

ALAN GARBER, MD, PhD, FACE: I don't like to start the maximum dose. So I would start at a smaller dose and dose escalate. Whenever you have metformin, you have to do that anyway, just to minimize the gastrointestinal side effects.

In the study that I mentioned, we actually started with only a single 500 mg metformin that took 2 mg of rosiglitazone with it.

CARLOS R. HAMILTON, JR., MD, FACE: Right. Now in the event that this combination of metformin and the thiazolidines is not adequate to get your hemoglobin-A1c down to where you would like for it to be, down to the 6.5% or 7%, what is your next step? Glenn, what do you usually do after that?

GLENN CUNNINGHAM, MD: So in the past, I think that I would have most likely gone to either insulin or to a sulfonylurea. Now I'm more inclined to seriously consider using one of the DPP-4 inhibitors in lieu of using sulfonylurea. So I think it depends on the patient, of course, but I think in the setting where patients want to continue with oral agents, then I would be more likely to use a DPP-4 inhibitor.

If they're really overweight, which many of these people are, one might even consider using a drug like Byetta. Obviously, you have many of the advantages there, but you have some disadvantages in terms of injection and the nausea and occasional vomiting that's associated with it.

CARLOS R. HAMILTON, JR., MD, FACE: Just for the sake of completeness, sulfonylureas, of course, was the original oral hypoglycemic agent, and it is still widely used. But you seem to indicate that that would not be one of your drugs of choice. Is that correct?

GLENN CUNNINGHAM, MD: I'm getting away from it for at least two reasons. One Alan mentioned, the durability of control with a sulfonylurea seems to not be good. That was true in the UKPDS study. It's true in the recent study that Alan just mentioned.

On the other hand, hypoglycemia tends to be more commonly seen with that agent, and particularly in older patients, I'm more cautious about using it for that reason.

CARLOS R. HAMILTON, JR., MD, FACE: But in patients, for example, that do have renal insufficiency, and one of the problems with thiazolidines is fluid retention, if they tend to have problems with fluid retention and with renal insufficiency, then sulfonylureas, at least in very low doses, might be an appropriate...

GLENN CUNNINGHAM, MD: That certainly is a consideration.

CARLOS R. HAMILTON, JR., MD, FACE: A consideration.

GLENN CUNNINGHAM, MD: I do think that edema and weight gain are reasons to be cautious in initiating treatment with TZDs.

CARLOS R. HAMILTON, JR., MD, FACE: What is your next step if these first groups of drugs don't produce the effect, Alan?

ALAN GARBER, MD, PhD, FACE: Well I agree with Glenn. I really have shied away from using sulfonylureas. Renal insufficiency is a relative contraindication for a number of the longer-acting agents, particularly glyburide.

CARLOS R. HAMILTON, JR., MD, FACE: Yes.

ALAN GARBER, MD, PhD, FACE: So I prefer to use either incretin agonists like Byetta, which is exenatide, and there'll be newer versions of that coming out shortly, or the DPP-4 inhibitors.

The difference, if you can take the injections, which none of my patients seem to object to, is the potential for significant weight loss with exenatide.

The DPP-4s are for people who want an oral agent or a once-a-day agent. There is no weight gain. They're completely weight neutral, and there is no hypoglycemia. Now that's a very easy-to-use, effective treatment program, but it's not going to work for patients whose A1cs are above 8.5% on two oral agents, such as metformin and a thiazolidinedione.

So if they're above 8.5%, this is not what I would do. Only if they're below 8.5%.

CARLOS R. HAMILTON, JR., MD, FACE: So the 8.5% is the cutoff for effectiveness of the DPP-4 type drugs, is that right?

GLENN CUNNINGHAM, MD: Or any if you're on oral agents and you can't control with, say, two oral agents and an A1c better than 8.5. Then I think we're...

CARLOS R. HAMILTON, JR., MD, FACE: You're just not going to get there.

GLENN CUNNINGHAM, MD: ...all thinking that we need to have insulin onboard.

CARLOS R. HAMILTON, JR., MD, FACE: Right. Okay. Do you think Byetta would be something you might try, especially for the overweight patient, before you would try insulin or not?

GLENN CUNNINGHAM, MD: You may be buying some time there. If they get really significant weight loss, it may be sufficient, but that's less likely, I would say.

CARLOS R. HAMILTON, JR., MD, FACE: One other class of drugs we haven't even mentioned, and it doesn't get mentioned very much in the United States, are the glucosidase inhibitors.

GLENN CUNNINGHAM, MD: Right.

CARLOS R. HAMILTON, JR., MD, FACE: Do you ever use those, or do you think they have a role in the management of any of these patients?

GLENN CUNNINGHAM, MD: So I personally was involved actually with some of the initial phase II and III studies with these agents, but they're not very easy for people to take, number one.

I do think that older patients who have mild hyperglycemia and who have constipation are good candidates for these drugs.

ALAN GARBER, MD, PhD, FACE: And for patients who just absolutely, positively won't go further than an oral agent, then I use those fourth line.

GLENN CUNNINGHAM, MD: Right.

CARLOS R. HAMILTON, JR., MD, FACE: So it's an adjunct, but it's not a...

GLENN CUNNINGHAM, MD: Not a common one.

CARLOS R. HAMILTON, JR., MD, FACE: Not a commonly used drug.

GLENN CUNNINGHAM, MD: Right.

CARLOS R. HAMILTON, JR., MD, FACE: All right. So at what point do you then decide to switch somebody over to some other treatment, presumably insulin? Alan, what are your criteria for that?

ALAN GARBER, MD, PhD, FACE: Three agents, not successful to goal, or two agents and A1cs of 8.5% or higher, they go to insulin.

CARLOS R. HAMILTON, JR., MD, FACE: And Glenn, do you agree with that?

GLENN CUNNINGHAM, MD: I agree with that.

CARLOS R. HAMILTON, JR., MD, FACE: And what is your initial response? What is your first...

GLENN CUNNINGHAM, MD: Approach to that, yes.

CARLOS R. HAMILTON, JR., MD, FACE: ...insulin -- insulin prescription?

GLENN CUNNINGHAM, MD: So several years ago, we were involved with some studies in which we used NPH, and actually I did that at the initiation of one of our fellows. And lo and behold, 50% of patients had A1cs that were under 7% with a single injection of NPH.

Now I think with other insulins available, I would prefer to go with a longer-acting insulin or possibly with a mixed insulin.

CARLOS R. HAMILTON, JR., MD, FACE: And this is given at bedtime.

GLENN CUNNINGHAM, MD: With a longer-acting insulin, I would give it at bedtime. If it's a mixed insulin, then I would give it at mealtime, dinner.

CARLOS R. HAMILTON, JR., MD, FACE: Yes. Give it before supper?

GLENN CUNNINGHAM, MD: Right.

CARLOS R. HAMILTON, JR., MD, FACE: Do you generally use one of the longer-acting ones, or do you prefer an NPH or some other combination?

ALAN GARBER, MD, PhD, FACE: You know, it produces equal outcomes. Either an analog premix before dinner or one of the newer analog long-acting insulins at bedtime will produce about the same number of patients getting to goal in terms of A1c and fasting blood sugars.

The real issue is what to do when that first injection fails, as it inevitably does because insulin is not going to retard the progressive nature of type 2 diabetes.

CARLOS R. HAMILTON, JR., MD, FACE: Do you continue the oral agents as you give the insulin like this?

GLENN CUNNINGHAM, MD: I would continue the sensitizers, so metformin and a TZD would be continued...

CARLOS R. HAMILTON, JR., MD, FACE: But there would be no reason to continue sulfonylureas if you were going to give that, or the DPP-4s, would you continue that?

GLENN CUNNINGHAM, MD: The DPP-4s have not been approved for use with insulin at this point, so I think we would say no. The use of sulfonylureas in this setting in general would be stopped. However, there is some data that suggests that you can get some increase insulin secretion that goes to the liver and may help control hepatic gluconeogenesis.

CARLOS R. HAMILTON, JR., MD, FACE: A lot of patients that are referred to me are on both insulin and sulfonylureas. And frankly, I have never been impressed that the sulfonylureas were doing very much for them, and it's just another pill to take.

GLENN CUNNINGHAM, MD: I would agree with that. I think it sort of complicates the picture.

CARLOS R. HAMILTON, JR., MD, FACE: Do you agree with that? Do you agree with that Alan?

ALAN GARBER, MD, PhD, FACE: Yes. I think sulfonylureas tend to act more like a basal insulin. They lower both the preprandial and the postprandial equally, and so you don't get compensatory reductions of the post-meal excursion, which is really what you want to try and get.

CARLOS R. HAMILTON, JR., MD, FACE: Well, this business about postprandial hyperglycemia is a whole 'nother topic that I think we've covered in some of these other programs and we might discuss that in a future Clinical Conversations because it's a whole 'nother ball game in terms of how you approach these patients.

All right. Well, I just want to thank both of you for being with us today. I think this has been a very helpful conversation, and I hope that our viewers share that feeling.

And Alan, thank you very much, and Glenn, I appreciate very much both of you being here. And thank you very much.

Again, I'm Dr. Carlos Hamilton, and thank all of you for watching. Thank you very much.