Managing Hyperlipidemia in Patients with Diabetes

CARLOS R. HAMILTON, JR., MD, FACE: Hello, I'm Dr. Carlos Hamilton. Welcome to the AACE Clinical Conversations. In this program, we will discuss managing hyperlipidemia in patients with diabetes. Joining us today to discuss this topic is Dr. Paul Jellinger, past President of AACE and past President of the American College of Endocrinology, and Professor of Medicine on the voluntary faculty at the University of Miami.

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

And also with us is Dr. Vijay Nambi, Assistant Professor of Medicine at the Baylor College of Medicine and at the Center for Cardiovascular Prevention at the Methodist DeBakey Heart Center in Houston. Thank you very much for joining us today.

Paul, what should be the goals of our management of hyperlipidemia in patients with diabetes?

PAUL S. JELLINGER, MD, MACE: Fortunately, we have good guidance on this from several important clinical trials over the last 5 to 10 years. Since we know that diabetes is a cardiac equivalent -- cardiac risk equivalent and the trials have supported this concept, an LDL goal of less than 100 is quite suitable and is indeed the goal for just about all persons with diabetes.

There is a growing interest in driving that LDL goal to less than 70, which is the goal for persons with diabetes that have had heart disease. But in individuals with diabetes that have not had heart disease, it remains a preferable goal or a reasonable goal, but not a necessarily mandatory goal.

In terms of triglycerides, it's particularly important to control triglycerides in individuals with diabetes because they're so frequently elevated, and the association of high triglycerides and low HDL is part of the insulin resistance or metabolic syndrome.

We believe that triglycerides should certainly be less than 150, and my personal believe is they should be approaching 100, if not less than that. So our goal is minimum or less than 150, ideal approximately 100.

CARLOS R. HAMILTON, JR., MD, FACE: And HDL levels?

PAUL S. JELLINGER, MD, MACE: HDL, higher the better. I like to shoot for an HDL goal of greater than 50.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Torre, what is your procedure for evaluating these lipids in these patients? How often do you check them and what do you check?

JOSEPH J. TORRE, MD, FACP, FACE: I think baseline screening at any age for diabetes should be done, and while one is using lifestyle modification to try to improve the lipid profile, measurement every three months is reasonable. While adjusting pharma -- medications to control the hyperlipidemia, practically speaking we use every three months, although practically we could do it a little bit sooner than that.

CARLOS R. HAMILTON, JR., MD, FACE: So in the routine assessment, you're talking about total cholesterol, HDL cholesterol, LDL and triglycerides. And those are the basic four tests that are performed in the fasting state.

Dr. Nambi, what is the importance of the differentiations of some of these LDL particles? We hear a lot about small dense LDL and other nontraditional components of the lipid profile. Should we be measuring those and what is their significance?

VIJAY NAMBI, MD: Carlos, that's an area of a lot of debate ongoing right now. The thing what we know from evidence that we have right now is small dense LDL is associated with worse disease or more events, coronary events and cerebrovascular events, for that matter.

What seems to be the concept or the hypothesis is the small dense LDL, they're more poorly cleared by the liver and also they get easier through the endothelial gap junctions to form atheromas. So there is a good amount of data supporting the fact that these small dense LDL are more pro-atherogenic.

Now the question is, "Do you have to measure them separately?" The thing is a non-HDL cholesterol, which is cholesterol in anything other than the HDL is a pretty good reflector of the total number of apo-B particles.

And what seems to be more supportive or more -- the evidence seems to support that the LDL particle number is probably more important than the size even. The higher the number of LDL particles, the worse the association with coronary artery disease is.

CARLOS R. HAMILTON, JR., MD, FACE: Do you think there is any clinical utility in actually measuring these small LDL particles?

VIJAY NAMBI, MD: So the guidelines would suggest that norm -- getting a non-HDL cholesterol is as good as getting an apo-B, but there are certain situations, like when your triglycerides go too high, that they don't track along as well as you would when you have a more normal triglyceride...

CARLOS R. HAMILTON, JR., MD, FACE: Well, that interferes with the measurement of the LDL.

VIJAY NAMBI, MD: Exactly. So in those situations, perhaps there is a role for apo-B. In other words, trying to get the total number of particles. But overall, if you treat your patient to targets, both your LDL and your non-HDL cholesterol, you simultaneously would reduce your particle number and you would have achieved that.

CARLOS R. HAMILTON, JR., MD, FACE: So from a therapeutic standpoint, if you can lower the total cholesterol and lower the LDL and hopefully raise the HDL, but certainly lower the LDL, you are achieving what you can -- what you can with this situation.

VIJAY NAMBI, MD: Absolutely. And the other, third component of that is the non-HDL cholesterol, which you know, takes into account the VLDL and the IDL particles, so the non-HDL cholesterol goal is normally about 30 more than your LDL goal. So if your LDL goal was 100, your non-HDL goal would be 130. If your LDL goal was 70, your non-HDL would be 100. It's about 30 more.

CARLOS R. HAMILTON, JR., MD, FACE: That's very helpful.

VIJAY NAMBI, MD: And that goes, again, back to the Friedewald formula where, you know, your triglycerides are divided by 5, so if your goal of triglycerides is 150, divide by 5. That's 30. So that's where most of it comes from.

CARLOS R. HAMILTON, JR., MD, FACE: Very interesting. We know that the level of the blood sugar has effects not only on the lipids but also on the vascular outcomes in diabetics. Paul, what is your -- what do you feel is the role of glycemic control in managing these vascular complications?

PAUL S. JELLINGER, MD, MACE: Well, in managing vascular complications, I think, of course for microvascular disease it's extremely important. And let me interject at this point that AACE has created a very useful tool for helping clinicians achieve glycemic goals, the AACE diabetes roadmaps, which can be downloaded and viewed from the AACE web site and they're very popular. That will help clinicians reach the A1c goal of less than 6.5.

In terms of glycemic control and the lipid parameters or the lipid abnormalities, that's an awfully good question because, unfortunately, there is a conception -- in my view a misconception -- that fine-tuning and correcting the level of blood sugar will normalize or near-normalize the lipid abnormalities and sometimes clinicians wait much too long, saying, "I'll deal with the lipids later once I get the glucose under control."

In reality, yes, triglycerides will respond to improved glucose control to a moderate degree. I don't think you're going to get a triglyceride level of 400 or 500 down to 120 just by correcting the glucose. But they will respond and that's something that needs to be -- you need to focus on glucose control largely for the improvement in triglycerides, which in conjunction with that, would be an increase in HDL.

But in terms of LDL cholesterol, there is no significant change at all in that result based on improving glycemic control. So I would urge physicians to not wait until a glycemic control is improved before approaching the lipid abnormalities because the degree of improvement is somewhat modest and you've wasted a lot of time.

CARLOS R. HAMILTON, JR., MD, FACE: I think that's a very important observation. Joe, we are aware of the fact that weight loss and exercise have beneficial effects on the lipids. Tell us a little bit about that. What sort of beneficial effects can you get, and to what extent can we expect to see that?

JOSEPH J. TORRE, MD, FACP, FACE: Compared to pharmacologic therapy, the degree of lowering of LDL cholesterol that we've seen with weight loss is relatively little -- relatively modest, I should say.

Certainly in our most obese patients, most sedentary patients, then weight loss and activit -- and exercise can have a fairly dramatic effect. And in that regard, bariatric surgery has certainly shown that the dyslipidemia can be completely cleared, as is often the case with the hyperglycemia.

CARLOS R. HAMILTON, JR., MD, FACE: There has certainly been the suggestion that exercise is one of the better ways to try to increase HDL. Does that -- does that seem to be supported by evidence?

JOSEPH J. TORRE, MD, FACP, FACE: Yes, I think it is. It to some extent is relatively weak evidence, but this -- the usual recommendation is 30 minutes or more of moderate intensity exercise for patients.

CARLOS R. HAMILTON, JR., MD, FACE: You mentioned bariatric surgery as an alternative. Have you had experience with bariatric surgery in diabetics? Has that been generally pretty positive?

JOSEPH J. TORRE, MD, FACP, FACE: Yes we have, and it's -- it's a very attractive alternative certainly for our very obese patients. It's the only therapy that has had a longstanding effect on weight loss, maintaining weight loss.

CARLOS R. HAMILTON, JR., MD, FACE: So its -- its beneficial effect is primarily due to the weight loss. I mean, there are not any other components to that that you're immediately aware of.

JOSEPH J. TORRE, MD, FACP, FACE: Well, I'm sure there are a number of factors that are associated with the weight loss, but I would say that's the common denominator.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Nambi, you had mentioned that if we can lower the LDL, we can improve endothelial dysfunction and improve vascular outcomes. Do the statin drugs have any other protective effects on this other than lowering lipids? There has been some suggestion about that.

VIJAY NAMBI, MD: There has been a lot of research on statins and the so-called pleiotropic effects of statins. They definitely seem to -- there is a lot of suggestion that they seem to decrease inflammation, which as we all know is one of the chief drivers of atherosclerosis.

And if you want from a clinical perspective, cholesterol is not thought to be a risk factor for stroke. Pre -- a lot of epidemiological studies have not shown cholesterol to be a risk factor for stroke, but clearly statin therapy decreases strokes. So you would wonder if there is another mechanism in play there that having statins, you know, causing to do this.

They are studying this in the form of a study called JUPITER where they're looking at a statin and the target is lowering CRP, which as we know, is a nonspecific marker of inflammation.

CARLOS R. HAMILTON, JR., MD, FACE: Well, what if the statins and other medications that are commonly used, the fibrates and so forth, don't work. What else do you do?

VIJAY NAMBI, MD: Well, as far as taking care of your LDL cholesterol, I mean, then you come back down to lifestyle modifications, which is going to be crucial. Then other than that, you have your other non-statin approaches, which include ezetimibe. Then you have ... colesevelam, a bile acid resin. Then you have niacin even can in -- have a good -- a moderate effect on that.

Then there are plant stenols which are over-the-counter, but there are plant stenol ways. All of these give you very moderate -- you know, modest amount of reductions in your cholesterol.

Statins are -- you know, if you can, you should try to get the person on a statin. If that's not possible, you try to amalgamate these different other approaches and suggestions...

CARLOS R. HAMILTON, JR., MD, FACE: So some of these older techniques still are in play, especially if patients are not able to tolerate the statins, for whatever reason.

VIJAY NAMBI, MD: Absolutely.

CARLOS R. HAMILTON, JR., MD, FACE: What about the triglyceride level Paul? Is this something that is as important or how vigorously do you treat that?

PAUL S. JELLINGER, MD, MACE: Well, it's -- it's been a matter of great debate for some time just what the role of hypertriglyceridemia is in cardiovascular risk. The evidence, again, is mounting that triglycerides, which are carried by the VLDL lipoprotein, in fact, is a direct cardiovascular toxin, in a sense, and we do believe that lowering triglycerides improves endothelial function.

And of course by doing that you raise HDL. They're always in inverse ratio, so that if for no other reason, lowering triglycerides, raising HDL, it's a benefit. But there appears to be a growing body of evidence that hypertriglyceridemia and probably postprandial hypertriglyceridemia is particularly important.

CARLOS R. HAMILTON, JR., MD, FACE: Okay, so weight loss and control of the blood sugar improve triglycerides. After that...

PAUL S. JELLINGER, MD, MACE: Then you need to use a variety of agents.

CARLOS R. HAMILTON, JR., MD, FACE: ...the standard drugs are -- or what can you use?

PAUL S. JELLINGER, MD, MACE: Statin drugs have a modest effect on triglycerides -- some more than others, but sometimes you can reach the goal of less than 150, or as I said, really closer to 100 with statin drugs.

But often or not you need to combine statin drugs with either fibrates or niacin in order to get the final degree of tri -- triglyceride lowering and HDL raising to -- to perfect the lipid pro -- profile and get the triglyceride level down and HDL up.

CARLOS R. HAMILTON, JR., MD, FACE: And if niacin doesn't work as effectively as you would like for it to, are there other things? We hear a lot about omega 3 drugs.

PAUL S. JELLINGER, MD, MACE: Well, first of all, niacin, I think, will always work. It's just not always able to be tolerated. So if -- I think maybe we might say, "If a patient can't tolerate niacin, what do you do?"

Omega 3s are very useful at high doses for lowering triglycerides. They are recommended at lower doses as an antiarrhythmic, nonspecific benefit -- cardiac benefit, but at higher doses they do lower triglycerides and raise HDL some, and that is a useful tool.

CARLOS R. HAMILTON, JR., MD, FACE: And those are rather well tolerated.

PAUL S. JELLINGER, MD, MACE: Yeah, they're well tolerated and they're inexpensive. The prescription brand is more expensive than the over-the-counter, perhaps a bit purer and more -- it's more concentrated.

CARLOS R. HAMILTON, JR., MD, FACE: So these lifestyle changes, treatment of the cholesterol with the statins, also benefitting the triglycerides to some extent, and then niacin pushed to maximum doses tolerated or the fibrates, of course, and then the omega fatty acids.

So we -- we have a number of alternatives here to try to achieve these goals.

VIJAY NAMBI, MD: One point I want to make about fish oil, the omega 3 fatty acids, the over-the-counter medications, you have to be careful because they always advertise them as 1,000 mg, etc. It's the omega 3 component that's most important.

So as Dr. Jellinger was mentioning, the prescription forms have more concentrated forms, so the person has to know the number of medications, the number of tablets you need to get to that 3 to 5 gram a day dose that...

PAUL S. JELLINGER, MD, MACE: And it's a lot, right?

VIJAY NAMBI, MD: ...he was mentioning. Yeah.

PAUL S. JELLINGER, MD, MACE: It's six or eight tablets of the over-the-counter and two to four -- four of the prescription.

CARLOS R. HAMILTON, JR., MD, FACE: That's a lot. Well, that's very helpful information. I think that a lot of our viewers will find that to be very useful in their practices.

I want to thank all of you for being with us today. This has been a very useful presentation, and I want to thank all of you for listening. Again, I'm Dr. Carlos Hamilton.