Prevention of Vascular Complications in Patients with Diabetes Mellitus

CARLOS R. HAMILTON, JR., MD, FACE: Hello, I'm Dr. Carlos Hamilton. Welcome to the AACE Clinical Conversations. In this program, we will be discussing the prevention of vascular complications in patients with diabetes mellitus.

Joining us today for this program is Dr. Paul Jellinger, the past president of AACE and past president of the American College of Endocrinology, and clinical professor on the voluntary faculty at the University of Miami.

Also here is Dr. Joseph Torre, a Senior Endocrinologist at the Buffalo Medical Group and Assistant Clinical Professor at the State University of New York in Buffalo.

CARLOS R. HAMILTON, JR., MD, FACE: Also here is Dr. Vijay Nambi, Assistant Professor of Medicine at the Baylor College of Medicine and the Center for Cardiovascular Prevention at the DeBakey Methodist Heart Center in Houston. Thank you very much for joining us today.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Torre, can you define the importance of type 2 diabetes as a risk factor for vascular disease?

JOSEPH J. TORRE, MD, FACP, FACE: Carlos, as most people who are likely to view this conversation know, the major cause of death in patients with diabetes is cardiovascular disease. It's sort of become a buzz word that the risk of developing a cardiovascular event if you have diabetes is the same as having a recurrent event if you already have established coronary artery disease.

CARLOS R. HAMILTON, JR., MD, FACE: Uh huh.

JOSEPH J. TORRE, MD, FACP, FACE: The incidence of diabetes in this country as of a couple of years ago -- the last national survey -- was approximately 7% of the population and in certain minorities, up to 25% of the population.

Perhaps -- or as importantly, the -- it's estimated that double that number have latent or perhaps -- or pre-diabetes, so our challenge is clearly to find and implement methods of preventing progression of this condition.

CARLOS R. HAMILTON, JR., MD, FACE: What -- what is your opinion about the factors that contribute to the high incidence of vascular disease in our patients with diabetes?

JOSEPH J. TORRE, MD, FACP, FACE: Carlos, dating back to the MRFIT data, the absolute risk of cardiovascular disease in men with diabetes is three times that of men without diabetes.

There is also a very clear relationship to systolic blood pressure levels. This -- these data and others strongly suggest that high -- high blood pressure may, in fact, be of paramount importance in the development of vascular disease and diabetes. But it's also clear that this shares common mechanisms, primarily of endothelial dysfunction with the other associated comorbidities with diabetes, particularly hyper -- dyslipidemia or hyperlipidemia, perhaps hyperuricemia, frequently chronic kidney disease.

And oftentimes, the poor cardiopulmonary status and nutritional status of a lot of our patients is usually associated with obesity.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Jellinger, how would you rate the importance of these various factors?

PAUL S. JELLINGER, MD, MACE: Well, that's a question that's been asked by many people in terms of ranking which risk factors are the most important. There is no clear answer on that.

Many of us believe that hypertension may be the most powerful driver of the cardiovascular risk, but clearly dyslipidemia and elevated blood sugars play a role.

As endocrinologists, we focus a great deal on controlling blood sugar, but in reality, that may lag -- may lag behind the control of blood pressure and the control of lipids and its actual contribution to macrovascular disease, although recent evidence is suggesting progressively that glycemic control does play a role in macrovascular disease. So blood sugar control is emerging as a very important risk factor as well.

But I think most of us would probably rate control of blood pressure first and lipids second -- very close -- closely followed by blood sugar.

The good news is that an important study, the Steno-2 study, published three or four years ago, showed that by targeting each one of the risk factors we've been talking about, blood sugar, blood pressure and dyslipidemia, even not reaching goal, but just affecting their levels, bringing it down, there was a 50% reduction in subsequent complications. So there is good evidence that targeting all of these really makes a difference.

CARLOS R. HAMILTON, JR., MD, FACE: What do you do in your evaluation of these patients to assess these various risk factors?

PAUL S. JELLINGER, MD, MACE: Well, persons with diabetes need really detailed attention to these -- to these risk factors. Exquisite control of the blood pressure and lipid levels is really very, very important.

I mean, I check blood pressures, of course, like everyone else does, at each visit more than one time, and often enough have patients come in between visits for blood pressure checks or on occasion ask the patient to buy a blood sugar machine, which are not very expensive and do it at home.

CARLOS R. HAMILTON, JR., MD, FACE: Blood pressure machine.

PAUL S. JELLINGER, MD, MACE: A blood pressure machine.

PAUL S. JELLINGER, MD, MACE: And report back a series of readings. I like to keep the blood pressure in persons with diabetes less than 130/80 if possible. The lower the better.

In terms of lipids, you know, I don't believe it's really enough to check a lipid profile in someone with diabetes once-a-year. I think we need to do that more often. I would say as a minimum probably twice-a-year.

Things change a lot in people with diabetes. And of course, when we make changes in their treatment options or we add medications or if an intercurrent illness has taken place, there is reason to check the lipid values even more often when a new drug has been added for...

CARLOS R. HAMILTON, JR., MD, FACE: If you make a change in a person's medication program for hyperlipidemia, how often will you recheck their lipid profile after making that change?

PAUL S. JELLINGER, MD, MACE: Generally, when I make a change, be it the dose of statin or adding a new drug, a fibrate or niacin or whatever the change may be, I will reevaluate that result in six weeks. I will look at their lipid profile in the fasting state, and I will also, of course, look at the liver function test and creatinine kinase to make sure that the change hasn't resulted in any elevation of enzymes.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Nambi, what is your opinion about the role of hypertension and abnormalities in lipids in these patients with type 2 diabetes?

VIJAY NAMBI, MD: I think Paul and Joe have really beautifully laid it out as to the importance of both these in control of -- risk of vascular disease in diabetes.

There have been other studies that have shown that having diabetes -- you know there are -- there are different kinds of diabetics. There are those who have a very high risk for macrovascular disease or atherosclerotic disease, and there are some who don't.

For the sake of simplicity, considering anybody with diabetes as being high risk equivalent makes a lot of sense. Because people don't -- I know if you go and ask an average doctor, "Do you do the Framingham risk score," the answer is no. They find it tedious, and although it's easy enough to get the tools to do it, the answer is they don't do it that often.

It's probably useful to kind of categorize risk that way, but overall, considering diabetes as a high risk equivalent is very important. It's borne out also in the guidelines. If you look at the blood pressure guidelines, diabetes is the only state wherein there is a specific, different cutoff for blood pressure compared to the other with hypertension, the same way getting the lipids and the LDL goal less than 100, for sure -- you know, considering that is a risk equivalent is very important.

So I just want to emphasize both what Paul and Joe have discussed here and control of risk factors is absolutely important in diabetics.

CARLOS R. HAMILTON, JR., MD, FACE: In the management of our diabetic patients, we often emphasize weight control and the management of obesity. But there has been a lot of interest in the distribution of obesity and its effect on diabetic patients and in their outcomes, especially the intra-abdominal obesity. Tell us a little bit about that Paul?

PAUL S. JELLINGER, MD, MACE: Well, there are many, many studies to suggest that the -- the deposition of fat in the viscera, the so-called visceral adiposity, is uniquely harmful to the patient not only with diabetes, but in patients without diabetes who may have metabolic syndrome or insulin resistance. And it appears to hold up in study after study.

Why that happens is not completely clear, but clearly the deposition of fat in the viscera is associated with very aggressive release of free fatty acids or a strong efflux of free fatty acids that are really toxic to the endothelium, toxic to the beta cell, etc., etc.

And it would appear that one of the major bases for visceral adiposity being harmful is in a greatly enlarged pool of circulating free fatty acids.

CARLOS R. HAMILTON, JR., MD, FACE: Smoking would have to be one of the risk factors for vascular disease in all patients, but for some reason or other, diabetic patients seem to be particularly susceptible to the effects of smoking. Has this been your experience?

JOSEPH J. TORRE, MD, FACP, FACE:

I must confess that I have promised in some ways not to hurt myself hitting my head against the wall trying to get patients to stop smoking and lose weight, but clearly such intervention is necessary and it's probably the linchpin in lifestyle modification.

So what I like -- what I do mostly, of course, is mention it at every visit, and weight is almost always the first thing that comes up if they're overweight.

But I try to take advantage of whatever the patient's insurance plan has to offer in terms of smoking cessation programs, in terms of exercise programs, and certainly in terms of dietary counseling.

CARLOS R. HAMILTON, JR., MD, FACE: You know, I don't have any statistics to support this conclusion, but I am convinced that the effects of cigarette smoking and diabetes are synergistic in a bad way for our patients, and that you rarely see ischemic peripheral vascular disease leading to amputations in diabetic patients unless they also smoke.

And I try to emphasize that to my patients as a motivation, and it sometimes is effective. Has this been your experience?

PAUL S. JELLINGER, MD, MACE: Yeah, absolutely. Smoking is associated with low levels of HDL that you cannot increase while you're smoking.

CARLOS R. HAMILTON, JR., MD, FACE: What -- what are your goals for lipids in our patients with diabetes? You mentioned HDL and triglycerides a minute ago. What sort of goals do you set for these patients?

PAUL S. JELLINGER, MD, MACE: Well, I think we're all very familiar. We -- we tend to follow the NCEP/ATP-III recommendations, and if an individual has diabetes, we are automatically tuned into an LDL goal of less than 100. What's increasing in interest is whether or not we should actually drive that goal down to less than 70 for all persons with diabetes.

PAUL S. JELLINGER, MD, MACE: However, it needs to be made clear that the only strong recommendation for less than 70 is diabetic persons who have had cardiac disease, not just all individuals with diabetes.

So an LDL less 100, in some cases less than 70, and that's of growing -- of growing interest.

Triglycerides should be certainly less than 150. I even like to look at 100 or less than that as really an ideal level. Probably 90 or 95 is ideal and HDL as high as you can get it, over 50 as a minimum.

CARLOS R. HAMILTON, JR., MD, FACE: Vijay, tell us a little bit about endothelial dysfunction and how this -- these things interact.

VIJAY NAMBI, MD: The thing with, you know, endothelial dysfunction is it's been strongly associated with coronary artery disease and atherosclerotic vascular disease. And what mediates it is pretty much any of your standard risk factors.

In fact, in some of the studies that were eloquently done, what they did was they took normal controls and had them just take a huge fat load. You know, a different food source with a huge amount of fat load.

CARLOS R. HAMILTON, JR., MD, FACE: Excuse me, this endothelial dysfunction following a high fat intake is monitored by ultrasound studies of the endothelium?

VIJAY NAMBI, MD: Absolutely. There are a few ways to monitor them. The one that is most commonly used in research is the brachial artery reactivity testing. That's the one that's used, and that's what they used for this one too.

CARLOS R. HAMILTON, JR., MD, FACE: And are there specific lipid therapies that affect this, this endothelial dysfunction?

VIJAY NAMBI, MD: Well, the good thing or the bad thing, your perspective, is that treating the standard risk factors the way we do normally tends to improve the endothelial function on its own. So your statins do -- so the usual things that we use tend to improve the endothelial function.

That's good in a way because you know we're doing what we can. You know, if you had another way to target it, it would be great too if you can overall improve the vascular risk. But the traditional things, you know, weight loss, that's very important. Exercise that improves the endothelial function, lipid-lowering, blood pressure control -- all of these do improve endothelial function.

CARLOS R. HAMILTON, JR., MD, FACE: When we're talking about vascular complications in patients with diabetes, Paul, we would be remiss if we didn't mention some of the controversy about the glitazones medications, which is so commonly discussed nowadays.

What -- what are your feelings about this and how do you approach it?

PAUL S. JELLINGER, MD, MACE: Well, I think as all the viewers are aware, rosiglitazone, one of the TZDs available, has been -- has been accused of, in a sense, or written about in terms of increasing cardiovascular risk based on a very large meta-analysis in The New England Journal.

This has taken off a life of its own. It's been in the press, and as everyone knows, has received huge levels of publicity.

There are issues on both sides of this. I think it's fair to say that -- that there may be a signal out there that rosiglitazone enhances cardiovascular risk, but note my words. There may be a signal.

The data is all based on meta-analysis. The kind of trials that will tell us whether there is an increased risk of cardiovascular events using rosiglitazone are prospective clinical trials of which we do not have data telling us one way or another that there is an increased or a decreased cardiovascular risk. So I think the jury is still out.

Unfortunately, the publicity has been so widespread that patients are very fearful, and physicians too in many cases, to continue rosiglitazone until this data is available, which we hope we'll have in a few years.

So all I can say at this point is it's trial by press. It's a concern, a signal, but it is by no means proven at this point that rosiglitazone is associated with increased cardiovascular risk.

PAUL S. JELLINGER, MD, MACE: I think we should -- we should clarify the difference between the heart failure risk of TZDs and this reputed coronary risk issue with rosiglitazone. Both glitazones can be associated with enhancing congestive heart failure in a patient who is predisposed to congestive heart failure, has a damaged myocardium because they increase intravascular fluid volume.

It's not a cardiac effect. It's a volume effect. If an individual's heart is strong enough to deal with the increased volume, there will be no issues. But that's shared by both glitazones.

CARLOS R. HAMILTON, JR., MD, FACE: I think that's a very important distinction. In patients that you are treating with glitazones, if they start developing edema, is that a sign that you need to stop that medication or...

PAUL S. JELLINGER, MD, MACE: Not really. I mean, that's a problem. Physicians interpret edema as heart failure much too readily and there is edema and then there is congestive heart failure with edema.

PAUL S. JELLINGER, MD, MACE: And just having peripheral edema on a TZD usually does not mean heart failure. That's a separate process.

CARLOS R. HAMILTON, JR., MD, FACE: Well, I really do appreciate your all being with us today. This has been a very useful and helpful conversation. And thank all of you for watching. Once again, I’m Dr. Carlos Hamilton. Thank you so much.