SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. References

A panel was convened on January 10, 2007, to discuss the challenges to the diagnosis, evaluation, treatment, and management of clustered cardiometabolic risk factors. George Bakris, MD, Professor of Medicine, University of Chicago, Chicago, IL, moderated the panel. Vivian Fonseca, MD, Tulane University Health Science Center, New Orleans, LA, and JoAnne Foody, MD, Harvard School of Medicine, Boston, MA, participated in the discussion. This expert panel discussion was supported by and each author received an honorarium from Merck & Co, Inc, and Sanofi-Aventis for time and effort spent participating in the discussion and reviewing the transcript for important intellectual content before publication. The authors maintained full control of the discussion and the resulting content of this article.


DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Today we're going to talk about the challenges of managing the cluster of cardiometabolic risk factors and their diagnosis, evaluation, and treatment. Let me start off with you, Vivian. What are the risk factors that we should target in this growing epidemic of obesity?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

Well, clearly we have a major epidemic of obesity that has many subsequent downstream consequences, including diabetes and its microvascular complications, as well as cardiovascular (CV) disease. So our aim should be 2-fold to prevent the progression of obesity to diabetes as well as to prevent the development of CV events. There are multiple risk factors associated with obesity and we need to recognize all of them and target as many of them as possible to prevent progression of the disease. These include the common things like hyperglycemia, blood pressure (BP), and lipid abnormalities, which classically include high triglyceride and low high-density lipoprotein (HDL) cholesterol levels. Low-density lipoprotein (LDL) cholesterol also remains a prime target due to the relative ease with which it can be treated with very good outcome data. In addition, we need to consider the use of aspirin and angiotensin-converting enzyme (ACE) inhibitors in high-risk individuals. Finally, I want to emphasize the importance of lifestyle change because exercise and modest degrees of weight loss can improve many of these risk factors. Once we deal with these, we can go beyond that to think about those nontraditional risk factors but I think these are essential to get started.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Thanks. JoAnne, do you want to add anything to that?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

Certainly, as Dr Fonseca has emphasized, the risks associated with obesity as well as the consequences of diabetes and hyperglycemia are multifactorial. We must move beyond thinking about these disease states in their individual silos but look at them as clustered and contributing to global risk. Hyperglycemia, hyperinsulinemia, dyslipidemia, and hypertension all tend to cluster and are associated with an inflammatory milieu that promotes atherosclerosis. We need to address all of these risk factors in concert and develop multifactorial approaches in an effort to reduce the CV risk associated with these conditions.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Well, I think we'd all agree that everything that you've both said is on target. The problem is that every nonpharmacologic lifestyle intervention has worked in the short-term and failed in the long-term. That includes dietary therapy, exercise, and a whole host of other interventions. It is by far the minority of people who actually stick with these programs and have superior success, so there's no question they do work if they are adhered to, but the problem is that most people don't adhere to them. Moreover, and I'm going to make a bit of a political statement now, if you actually track obesity rates and the development of the metabolic syndrome, it closely parallels the omission of physical education programs and the increase in the use of computers and, hence, a more sedentary productive lifestyle mentally, but physically the lack of emphasis on key issues. Vivian, do you honestly think we can achieve major inroads in sustaining or improving adherence to lifestyle interventions without any kind of central intervention (ie, governmental policy changes)?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

I think we need some policy changes and we need societal change. But there are some important lessons we can learn from major clinical trials such as the Diabetes Prevention Program (DPP) both in the United States and in Finland. The DPP was recently successful in getting people to increase their physical activity to a point that most people can manage, which is walking 30 minutes a day.

The Finnish Diabetes Program taught us a very important lesson in their follow-up study. They had a structured and repeated intervention for lifestyle change over 3 years and showed that those people who were successful over the 3 years with repeated interventions were then able to maintain that lifestyle change for a further 3 years. So, I think that's a reasonable long-term follow-up.

There's a National Institutes of Health (NIH) trial called “Look Ahead” that is investigating weight loss strategies in people with diabetes who have demonstrated significant reduction in weight over a 1-year period. Whether that will lead to a reduction in events and can be sustained over the long-term, we'll have to see.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Thanks. JoAnne, do you want to add to that?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

I would have to agree that as much as we need to develop national policies to address this, we need to look at both an individual- as well as a population-based approach to combatting this. We do have very sound evidence that interventions such as DPP as well as all our medical interventions are highly effective in reducing risk in this population. But, again, to speak to your point, this issue of adherence, whether it's adherence to lifestyle interventions or even medical interventions, is a major issue and we need to develop strategies in a systematic way that will promote adherence in our patients.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

No question, I think we're all on target with that. JoAnne, let me ask you something about the evolution of heart disease in patients with type 2 diabetes with a specific focus on women. It's pretty clear that the incidence of heart disease and morbid events is much higher among those with diabetes than the nondiabetic cohort, but having said that, it's also clear that postmenopausal women have much higher event rates shortly after menopause than men. I'd like you to just talk about that a little bit in the context of whether we should be more aggressive in managing risk factors in women in the perimenopausal period and what is the role of estrogen and other related issues.

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

Absolutely. As you've said, we recognize that diabetes is associated with very significant CV event rates. What may not be recognized is, as you've said, that diabetes is one of the most significant risk factors in women, much more so than men. In fact, diabetes levels any advantage that women may have relative to the presence of estrogen. A woman with diabetes has the same risk for MI as a man of the same age without diabetes.

So, for women, the CV risks attendant with diabetes are much higher and we need to address strategies, we need to address CV risk, much earlier in women. We need to address women who have gestational diabetes, for example, as a risk factor for the ultimate development of diabetes and be more cognizant of the interplay of insulin resistance and the metabolic syndrome and the range of risk factors, particularly in that perimenopausal period.

We have the advantage of very strong guidelines that have been put forth for women and CV risk prevention, which really challenge clinicians to maintain normal levels of BP, lipids, and glycemia throughout a woman's life span in an effort to really reduce the likelihood of CV events, particularly due to diabetes and the clustering of risk.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Thanks. It's well-known that if you actually achieve the goal for the 3 major risk factors, that is BP, glycemic control, and lipid management, you can achieve a 72% risk reduction in overall CV events. Lipid-lowering therapy has been touted in editorials and in some articles to actually trump BP lowering and glycemic control for specifically reducing myocardial infarction. I'd just like your thoughts on that. Vivian?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

Well, clearly it may not be that lipids are more important, but the fact that the lipid-lowering drugs that we've had in the past decade or so, particularly statins, have led very safely to great reductions in lipid parameters without causing any major side effects for patients, and that has led to better outcomes. Now, in contrast, it is much harder to lower BP with a single drug. Most of the hypertension trials have shown that you need at least 3 and, if you want to get some patients to goal, you need 5 medications, but patients don't tolerate this cocktail of medications very well. So that is challenging. So many people have not achieved goals, particularly for systolic BP. That doesn't mean that BP is not important.

Similarly for glucose, there is no trial that has demonstrated that normal glycemia or near-normal glycemia improves outcome because no one has ever achieved that. That doesn't mean that glucose is not important as a risk factor, it's just that we haven't had the tools to lower glucose as well as we've had with a variety of very effective drugs for hypertension and cholesterol that have been shown to improve outcomes.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

JoAnne, do you want to add to that?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

I would have to agree with Vivian. I think we recognize that we do need to treat multiple risk factors and, with respect to dyslipidemia, we have the most effective agents to reduce cholesterol. We also recognize that dyslipidemia is quite common in our patients with diabetes, and I think recent Centers for Disease Control and Prevention (CDC) estimates suggest that nearly three-fourths if not higher numbers of diabetics actually have dyslipidemia. So I think we have a very high prevalence, we have highly effective therapies and, when used appropriately, have the potential then to significantly reduce risk.

That being said, while we may think we are adhering to guidelines in practice, clinicians still underutilize these therapies in appropriate patients, are unlikely to meet goals with respect to lipids, and therefore may not adequately reduce risk in their patients. Further, a significant proportion of our diabetic patients are unaware that dyslipidemia is common or that dyslipidemia contributes to their CV risk, say, in an equivalent fashion to their glucose control.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

So, it's a failure of the physician to educate the patient? Is that what you're implying?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

Well, perhaps, but I think we have handled diseases very singularly and in silos. We have to recognize and make our patients aware that diabetes is a multifactorial condition.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

So we're very clear on the importance of managing all 3 risk factors, not just one. But let me extend the discussion to other lipid subfractions, not just LDL. While the bulk of the data deal with this variable, let me ask you each to comment a little bit on what you think about the relative importance of triglycerides, based on the data. Vivian, let me start with you.

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

Well, triglycerides are an important CV risk factor. They are very easily identified in patients with type 2 diabetes and obesity and very closely linked with body weight. The difficulty comes in interpreting the data from clinical trials because triglyceride lowering with the drugs that we have for triglyceride lowering have not had as dramatic an effect in lowering events as have the statins. And the best data that we have are from the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), which was actually performed in people who had low HDL cholesterol levels, and it just happened that gemfibrozil also lowered triglycerides, but that was done outside the context of statin use. None of those patients received statins. And that has to be set against the data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, in which the primary end point was not met, partly because there was a lot of statin use that was not initially planned for in the study patients and particularly in the control group. So, although there was a reduction in some of the secondary events in the FIELD study, the primary end point was not met.

With those sorts of mixed results, I would say that I think we still have to keep an open mind on triglycerides. We know that people with hypertriglyceridemia are at increased risk and we have to try to come up with best risk reduction strategy in those patients.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Thank you. JoAnne, agree, disagree?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

I would have to agree. The bulk of our data come from statin trials regarding LDL cholesterol reduction and, as Dr Fonseca has stated, there were attendant reductions in triglycerides on the order of between 10% and 30% in those studies. The VA-HIT, as was stated, is one of the few studies that had no change in LDL cholesterol but an increase in HDL cholesterol levels and a significant 30% reduction in triglycerides, as well as an associated (about 24%) reduction in CV death. So I think that addressing lipids is important. We appreciate that addressing lipids via statins with a reduction in triglycerides that's associated with it has been shown to be associated with event reductions. But whether targeting triglycerides alone is associated with improved outcomes, really remains to be determined. Hopefully we'll have data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which will look more specifically at these issues that is, assigning simvastatin 20 mg and fenofibrate vs placebo but, for now, as has been stated, the first choice for lowering LDL cholesterol levels is the statin. If we look at triglyceride lowering if a patient does have isolated triglyceride lowering, I think the best approach is glycemic control as a first priority and then perhaps using a fibric acid derivative to improve triglyceride levels.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Very good, because fibric acid derivatives are not exactly benign with regard to side effect profiles, and I think people forget the fact that glycemic control is a critical factor in affecting triglycerides.

Before we leave lipids, I just want to ask your opinion, and it is an opinion because the data outside of one trial are not completely in yet, but what about HDL cholesterol raising or cholesteryl ester transfer protein (CETP) inhibitors? Do you think they have a future in this situation with regard to CV events other than just raising HDL levels? I realize the Pfizer experience is probably not a good indicator because there were effects on BP and now I'm hearing that aldosterone potentiation may also have been a mechanism. I just want your thoughts on this. Vivian?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

Well, I think the statins have been a tremendous help but we have to think beyond statins now because, even after reduction in risk with statins, there still remains a significant degree of residual risk in some individuals, particularly those with diabetes and obesity. In those patients, low HDL cholesterol has been an important CV risk factor and, as we've said earlier, it has not been easy to raise HDL cholesterol to the degree that we would like. Most of the drugs that we have show modest elevations, so CETP inhibition does give you significant elevation in HDL cholesterol levels and has the potential to improve CV risk, but we need the outcome data. As you mentioned, there were problems with BP increases with Pfizer's CETP inhibitor. There may have been some issues with the type of HDL elevation: it may be that it raised the wrong type of HDL subfraction that was not entirely beneficial, so although there were spectacular elevations, it wasn't the kind that we wanted. We don't really know what the ultimate answer is to this question. It will have to come from long-term clinical trials.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Great. JoAnne, do you have anything to add to that?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

I believe that the HDL hypothesis is robust. Unfortunately, I think that we have not found agents that can raise HDL levels either in an efficacious way or, quite frankly, in a safe way currently given the initial CETP inhibitor experience. The hope would certainly be that newer agents down the pike with a better side effect profile than the current CETP inhibitor that was studied may prove beneficial, but we're certainly a long way off from outcome studies and really resolving the controversy in that class.

I think as far as diabetic patients go, we have to remember that the initial approach to HDL raising should be behavioral interventions, such as weight loss, increased physical activity, and smoking cessation, as well as glycemic control. But nicotinic acid, as much as that was associated with concerns about the potential to raise glucose levels, more recent studies have suggested that niacin may be effectively and safely used in our diabetic patients if they're monitored and used at a dose between 1 and 2 g daily. But, again, care should be taken. So, I think we still have a lot to learn about HDL cholesterol, particularly in how we may best modify it in our diabetic patients.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Right. I just want to reinforce what you have said. One of the best things that people can do in terms of lifestyle change to dramatically affect HDL cholesterol independent of any agent is exercise and cut their carbohydrate intake by 50%. That will have a huge impact on HDL and of course triglyceride levels because they go hand in hand. So I think these are very practical and important points that we need to emphasize, so thanks for referring to this.

I want to move over now to an area that I'm sure you're both very comfortable with: glycemic control. I want to address some issues. Almost everyone I know suggests that metformin be put in the drinking water based on DPP, but there is a concern with metformin use in people with renal insufficiency that the US Food and Drug Administration (FDA) has issued that if you have a creatinine level >1.5 mg/dL you really can't get metformin.

Now it turns out that there are scant data, predominately from case reports, that this is a “real” problem but no formal analyses have been done to date from large databases to assess this issue. It's guilt by association with phenformin. We are critically looking at our database among patients in the Diabetes Center at the University of Chicago, coupling our efforts in collaboration with the Kaiser database to see at what estimated glomerular filtration rate, not serum creatinine, this cutoff for use should be made. So far we have noted that there's a whole host of people that are taking metformin who have been doing just fine for years with glomerular filtration rates in the 40s and 50s. Now I realize, and Vivian, I know you're going to bring this up, there was a case report of lactic acidosis in Diabetes Care not too long ago, but that was a case report on someone who was fairly old and had fairly progressive kidney disease. So I guess I'm asking the question, should we, in the absence of data, limit metformin to those prescribing guidelines for metformin? I know you can't make any strong statements but I want your opinions.

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

I would disagree with you, George. I think we have to be absolute for a simple reason. Our basic Hippocratic principle is that we first do no harm. And lactic acidosis is associated with such a high mortality rate that you have to bear in mind that there have been reports…you're talking about reports in the literature…but the FDA has several reports of lactic acidosis that occurred after metformin became available and almost all of them were associated with renal impairment or other situations where the drug was contraindicated. Remember that you know you accumulate lactate but maybe not enough in those patients to get lactic acidosis until the patient gets critically ill.

But you talked about the benefits of metformin (the cardioprotective effects of metformin), and if you look at the data from the United Kingdom Prospective Diabetes Study (UKPDS), that benefit is actually quite small compared with the other drugs. It is significant compared with diet alone but it's not significantly different from sulfonylureas or insulin. So, in high-risk patients such as those with renal insufficiency, which is a risk factor for CV disease, we don't know whether metformin is protective. So why give a drug that has some risk of a very serious problem when we don't know whether it's going to be of benefit and when there are other drugs that are safe to use in that situation, such as some of the sulfonylureas and insulin?

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Fair enough. JoAnne?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

You know, George, I really do have to agree more so with Vivian on this one. I think that there have been some initial data showing potential benefit although the benefits of metformin were small. I think that when we look at the totality of evidence and potential side effects overall, we really need to be wary and understand that accepting the totality of potential benefit of metformin is really a leap of faith at this point and that the data, if we look at all end points including benefits as well as potential harm, it really has not been investigated to the degree where we should be comfortable, particularly in our high-risk patients as you've suggested, and in those with renal insufficiency and higher risk states, where we do have other agents that may be beneficial.

That being said, I think we still need a lot more information regarding the role of the variety of agents with respect to their ability to reduce the macrovascular complications of diabetes.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Very good. And, by the way, don't apologize. I purposely set that up because I, too, am cautious in that population. I did it for the purposes of discussion. But since we're talking about insulin sensitizers and agents that improve insulin resistance, obviously you both know that I was going to ask you about the glitazones and the controversy with that because it has spawned a whole host of editorials and the figures publishing it are controversial in and of themselves. We have David Nathan, MD, coming out saying “forget about pills, just go on insulin.” Is there a role for the peroxisome proliferators-activated receptor (PPAR) γs, Vivian, in the treatment of diabetes based on the current data?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

Well, first of all it depends what your philosophy is and what you're treating. If you want to treat hyperglycemia and try to get it to the goals that have been stated or as low or near normal as possible, then you're going to have to use insulin sensitizers such as metformin in some individuals, and very often metformin is insufficient. We know that in the UKPDS, despite the good results of metformin, only 14% of patients with diabetes remained well controlled after 9 years on metformin monotherapy. So you do need additional therapies.

There have been questions about the combination of sulfonylurea and metformin for many years. The glitazones have a lot of beneficial effects on insulin resistance and lowering glycemia, and if you look at data from the Diabetes Outcome Progression Trial (ADOPT), rosiglitazone turned out to be the most effective in maintaining glycemic control at the end of 5 years. So if your aim is to improve glycemic control, there's no doubt in my mind that this is a good choice of therapy.

Having said that, we have this question mark with rosiglitazone, particularly in some high-risk patients and patients treated with insulin, and I think we have to be a little cautious in these patients. This has to be balanced by the data from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE), which actually showed a reduction although the primary end point was not significant. That was a short duration, 3-year study, and the secondary end point of myocardial infarction, death, and stroke was significantly reduced.

So I think on balance, there is still a role for thiazolidinediones; they should be used cautiously. If a patient develops a lot of weight gain and fluid retention, they're not appropriate for that therapy, just like patients with renal insufficiency are not appropriate for metformin therapy.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Okay, very good. Before I come to you, JoAnne, I just want to bring up one issue since you brought it up, Vivian, and that's the issue of weight gain. Now there are data that were published last year in the Journal of the American Society of Nephrology that support the concept that activation of sodium hydrogen (antiporter) is the key factor that influences fluid retention with these agents. So use of spironolactone worked in this study to reduce edema, and amiloride would have worked even better. Interestingly, furosemide did not affect edema at all. I personally have experience with that and have seen amelioration of the edema to the point where patients are no longer symptomatic. So I'm just wondering what your experience is with that and what your thoughts are.

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

My experience is like yours and I agree with you that this is one possible approach. The difficulty I have is the risk of hyperkalemia, which often occurs in patients with diabetes and nephropathy, particularly when they're already taking an ACE inhibitor or an angiotensin receptor blocker. To add in something like spironolactone can be challenging.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

All right.

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

But other than that, I think that makes sense, and if you have a problem, you just don't use it.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Very good. JoAnne?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

I would have to agree that the potential complexity of drug regimens and the potential complications associated with these drugs are always a concern and we need to tailor therapies accordingly; for example, we need to identify patients, including those with baseline heart failure, who may not be candidates for the glitazones. You know, in cardiology, this has become incredibly controversial, not only around heart failure but also myocardial infarction. Recent meta-analyses have definitely demonstrated concerns with increased rates of myocardial infarction, particularly with rosiglitazone, but seem to suggest that there may be some heterogeneity and that pioglitazone may not have those kinds of effects with respect to CV or coronary heart disease events. I think the jury is still out and until we have a head-to-head trial if that even was to occur, it's difficult to know the truth, but from a cardiologist's standpoint, I think many physicians certainly feel more comfortable with pioglitazone in well-selected patients.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

That's a good point. I just want to quickly touch on the spectrum of agents within the PPARγ class. There is no answer to this, but there's certainly an implication from PROACTIVE and some other smaller studies that there may be differences within this class of agents. But if you look at it from a basic science standpoint, they both look phenomenal. They're anti-inflammatory and they reduce oxidant stress—I mean, there are all kinds of positive things. They reduce microalbuminuria and they even reduce BP to a certain extent and yet you have slightly divergent effects on CV events. The one place where they are somewhat different, although not dramatically so, is in their lipid profiles. And I'd like you to conjecture on this difference. I know you can't answer this definitively, but what do you think is the contribution of the difference in lipid profiles to the difference in apparent CV outcomes. JoAnne?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

We know that all thiazolidinediones (TZDs) increase HDL levels, but the real difference has to do with LDL levels and how they operate with respect to that. So if we look at rosiglitazone in general, it makes the LDL subfractions larger and more buoyant but raises LDL cholesterol and seems to have some variable effects on triglycerides. So it's been argued perhaps that this increase in LDL may account for some of the issues. Unfortunately, if we look at the numbers, I find it difficult to believe that that accounts for all the difference, but it is certainly something to think about as we think about the drugs and the differences between drugs.

Now, if we look at pioglitazone, it activates PPARα as well as PPARγ, so I think we also have to look at potential differences between PPARα and PPARγ activation and what that may portend for CV events.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Very good. Vivian?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

I agree with what JoAnne said. I think it is impossible to know whether it is due to this effect or some other effect. It is quite remarkable that many of the other important things that we think about in terms of vascular disease such as endothelial function, inflammation, etc, are all improved by rosiglitazone. I think at the end of the day we need to look at outcomes data from large clinical trials rather than this meta-analysis, which sends a signal but is really not definitive in my opinion. We have to wait for the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) and Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) studies to be completed before we can draw any conclusions here.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Okay, very good. Now I want to briefly talk about the glucagon-like peptide (GLP) compounds. These are the new agents on the block and there's been a large uptake and use at least in Chicago with this whole “glitazone controversy.” There's been a movement generally away from the glitazones and much more use of agents such as sitagliptin phosphate since that's the only agent in that class. Their effects on glucose seem to be similar to the PPARγ agents. Vivian, what are your thoughts on this? Do you agree or disagree in terms of that kind of strategy, the potential trends, in the future?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

I think it's remarkable that we have waited 5 years for some data to appear. We've looked at meta-analyses from several short-term clinical trials, ignored the long-term data and data safety monitoring board recommendations from BARI-2D and ACCORD, focused on results from a meta-analysis of short-term trials, and switched practice to a relatively new drug on which there is no long-term safety data.

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

I have nothing against the GLP-1 class of drugs and the dipeptidyl peptidase-4 (DPP4) inhibitors, and actually use them a fair bit. I hope that they turn out to be beneficial in the long-term but we just don't have long-term data, and so one can't really assume that there is proven safety. We assumed that there would be CV risk reduction with the TZDs. It turns out that, at best, they may be neutral. But to jump from one class to another because one is new whereas the other has side effects, I think is fraught with danger considering that, although we know that there are side effects with TZDs, we know what they are and that they have been well quantified and characterized. As we discussed, we know about the fluid retention and that there are certain types of diuretics that can be used to address it, so I'm not enthusiastic about switching from one class to another for this reason. Obviously DPP4 inhibitors and GLP-1 agonists have their own advantages, and I would use them for their strengths rather than the weakness of something else.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

JoAnne, let me ask you about another class of agents represented by exenatide. This agent works by a different mechanism than sitagliptin phosphate; it's injectable and weight loss is associated with its use in a subfraction of patients. I noticed that a lot of individuals in the general medical community are actually using it as a weight loss agent in people who have impaired fasting glucose. This drug is obviously not indicated for that purpose. Looking at metformin as an agent that increases insulin sensitivity and has weight loss as a side effect, what about exenatide in that regard. Exenatide can't be used if you're taking insulin; it's supposed to be for earlier treatment in the disease course. What's your experience with that and how do you use it?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

We must always use therapies that have a strong evidence base and whose use will ultimately improve outcomes. And I think we're still in very much the same boat here. Certainly exenatide has been approved since 2005 for the treatment of type 2 diabetes, and while we know it improves blood sugar control, we also know that there is associated weight loss with its use. Unfortunately, the mechanism for this action is unclear. Again, we need more information on whether this approach will ultimately improve CV outcomes vis a vis either glucose lowering or weight loss. While one can assume that there would be benefit, we just don't have the data to inform our decision making.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Vivian, I assume you agree with that.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Okay, very good. So, I want to finish in the few minutes that we have left here talking about my favorite risk factor, BP. I don't know whether you're familiar with the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, which was recently stopped early by the Data Safety Monitoring Board because of an efficacy benefit in one group. This is a large CV outcome trial that included almost 12,000 patients and was presented in March 2008 at the American College of Cardiology Scientific Sessions in Chicago, IL, This trial had a very large cohort of people with diabetes. The uniqueness of this trial is that it initiated BP lowering with fixed-dose combination therapy and is really looking at combinations of renin-angiotensin system (RAS) blockers with calcium channel blockers (CCBs) vs RAS blockers and diuretics.

The BP control data from the first year of the trial were published in Blood Pressure in 2007 and show the highest ever BP control rate of any clinical trial at 83%. But what's interesting is that in the cohort with diabetes, the BP control rate was still close to 50% at 1 year. Now that's the highest to my knowledge of any control rate of BP in any clinical investigation that early in the trial.

And so I'm setting you up, having just looked at the 2008 American Diabetes Association guidelines, to ask you whether we should be initiating therapy with combinations, not monotherapy, in people 20/10 mm Hg above goal, which, in the person with diabetes, would be a BP of 150/90 mm Hg as the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends. Vivian?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

I didn't quite fully get that question, George.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

The question is, if you have a patient who is more than 20/10 mm Hg above their BP goal of 130/80 mm Hg, per current guidelines, should they be started on combination therapy vs monotherapy? JNC 7 would say yes. Your thoughts?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

I think that's a very reasonable approach. This is the first trial to use that as initial therapy. We have some short-term trials in hyperglycemia using initial combination therapy, although we don't have long-term outcome data with combinations. I think that approach is going to increase in popularity. The only downside is if you are concerned about side effects of one of the components. But very often in hypertension we use a diuretic as one of the components and we know what the downside risks are.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Right. JoAnne?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

I think that in the management of hypertension, particularly in our diabetic patients in whom our targets are much more stringent, we undertreat our patients and fail to start at doses of therapy that allow us to achieve the targets or to consider combination therapy.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Now, there's been a lot of press over the past couple of years on the risks or possible risks associated with treatment of a known risk factor, ie, BP, with agents that worsen another risk factor, ie, glycemic control. This observation of increased risk for new-onset diabetes is not in everyone, of course, but in people with impaired fasting glucose who are obese. Certainly there are data suggesting that even if you pair an RAS blocker with a diuretic, you're still not protected against new-onset diabetes.1 So, I'd like your opinions on what you think that means in terms of overall CV outcome. Would you do better with a combination of 2 metabolically neutral agents, that is, an RAS blocker and a CCB, that got you to the same level of BP control as an RAS blocker and a diuretic? The ACCOMPLISH trial will address this by the way, but I don't know the answer. Vivian?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

I think everything that I'm saying is somewhat speculative because we don't know, but the data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed that although diuretics were associated with increased risk of getting diabetes, the protective effect of lowering BP sort of negated any CV risk associated with that new-onset diabetes. So, I think perhaps it doesn't make a huge difference. It may get down to individual preferences and cost. There are other advantages of using a diuretic with an ACE inhibitor, such as controlling potassium, but having said that, I don't think that there is sufficient data to make a strong recommendation one way or the other. I think just using a combination would be useful in getting more people to goal.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Right. Keep in mind that in ALLHAT, if patients did develop diabetes, they were treated and therefore one could argue that the additional pill burden for those patients, not to mention the new diagnosis, would affect their insurance rates.

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

Sure, I appreciate that.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Okay. JoAnne, what are your thoughts?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

I think first and foremost, we must control BP. Now, that being said, I tend to think that all things being equal, if you were to control BP to the same degree with perhaps an ACE/diuretic strategy compared with an ACE/CCB strategy, I think you'd be more likely—and, again, this is speculative—to see a benefit with the ACE/CCB strategy because of the lack of metabolic effects of the diuretic. If we look at guidelines from Europe and their approach, they focus on drugs that block the renin-angiotensin-aldosterone system along with a CCB in part to avoid side effects of other agents.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Right. We haven't discussed β-blockers. If you look at the most recent updates of various guideline statements, the vasodilating β-blockers, carvedilol and now nebivolol, really are pretty metabolically neutral and even in the European database that's the case. So the traditional β-blockers absolutely worsen glycemic control, but the vasodilating agents don't seem to have that effect and, again, are a little more expensive in Europe than the traditional β-blockers. So, you're right, they are not used as frequently and that was the whole point in trying to avoid them.

I just want to finish up by thanking you both for participating here and giving each of you a chance to discuss anything that we haven't mentioned. Vivian?

DR FONSECA:

  1. Top of page
  2. Abstract
  3. References

I want to emphasize the importance of multiple risk factor control. I think we've done each of those individually but we've got to do it collectively in the same patient, as well as remember the benefits of aspirin use. In addition, I think we have some exciting data coming out in the next couple of years when major clinical trials such as ACCORD and BARI-2D will report their findings and that may well change our approach.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Absolutely. JoAnne?

DR FOODY:

  1. Top of page
  2. Abstract
  3. References

I would like to emphasize that we have such a major epidemic of obesity, metabolic syndrome, and diabetes that it requires that we move beyond our current paradigms and look at ways that we as clinicians, researchers, regulators, and advocates for our patients can work together to try to identify ways to modify risk in a multi-disciplinary way so that we can improve CV outcomes for our patients with diabetes.

DR BAKRIS:

  1. Top of page
  2. Abstract
  3. References

Very good. I fully concur with both of you and want to thank you both for joining me today. I thought we had a really good discussion. Thanks a lot.

References

  1. Top of page
  2. Abstract
  3. References
  • 1
    Bakris G, Molitch M, Hewkin A, et al. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care. 2006;29(12):25922597.