Dyslipidemia: New Patients, New Targets, New Therapies

At an industry-sponsored symposium held in conjunction with the American Association of Clinical Endocrinologists’ 2003 Annual Meeting and Clinical Congress, three leaders in diabetes research and treatment reviewed new lipid guidelines, discussed incorporating these goals into practice, reviewed screening and diagnostic strategies available to identify and treat patients and identified methods and interventions for endocrinologists to use to improve patient care by improving adherence to treatment regimens.

This program was supported by an unrestricted educational grant from Merck and Co., Inc. and Schering-Plough Corporation.

Are the ATP III Guidelines Aggressive Enough? Implications of the Heart Protection Study

The clinical approach to coronary artery disease (CAD) has evolved over time. The latest guidelines, Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults also known as Adult Treatment Panel III (ATP-III), represents significant changes in targeting therapies.

While focusing on LDL cholesterol as the primary target, the guidelines also give guidance for HDL cholesterol and triglycerides. They recognized the importance of multiple risk factors in patients at higher risk for CAD and that diabetes is a coronary risk equivalent (CRE) in these patients.

The Framingham study looked at the impact of low HDL on CAD when stratified by LDL levels. Even those with LDL cholesterol at or near 100 had a heart attack risk 2.5 greater with low HDL (Neaton JD, et al. Arch Int Med. 1992;152:1490).

Other Framingham data emphasized the importance of triglycerides. The higher the triglyceride levels, the greater the risk for heart disease. (Castelli WP, et al. Can J Cardiol. 1988;4:5A)

A groundbreaking study by Haffner, et al established diabetes as a CRE in 1998. The results showed that the seven-year incident of myocardial infarction (MI) was 4% in those with no previous history. In those with a previous heart attack, risk for a second was 19%. Diabetics who had never had an MI had roughly the same risk for a first attack as those without the disease had for a second. (Haffner SM. NEJM.1998; 339:229)

This is a group, according to Vivian A. Fonseca, MD, Tulane University Health Sciences Center in New Orleans that should be treated as aggressively as patients who have already had an MI.

“Over the last few years there has been an epidemic of both conditions,” said Dr. Fonseca. “They have been so closely linked that we expect a worsening of the epidemic of CAD.”

Studies are beginning to show that patients have greater reductions in risk with therapy. The 4S Study (Scandinavian Simvastatin Survival Study) showed greater absolute and relative CAD reduction in diabetics versus non-diabetic patients treated with statins. There was a 42% reduction in total mortality (Pyorala K, et al. Diabetes Care. 1997;20:614).

“Perhaps this relates to the fact that diabetics start off at greater risk,” said Dr. Fonseca. “Those at greatest risk show a greater reduction in cardiovascular events.”

For years, it was thought fatty streaks were the early abnormality in atherosclerosis. Now it is being recognized that endothelial dysfunction (ED) may precede the streaks.

Endothelial dysfunction is closely associated with the metabolic syndrome and obesity, providing a possible link between CAD and diabetes. Many of the risk factors seen in patients with metabolic syndrome, such as dyslipidemia, hypertension, or diabetes also leads to endothelial dysfunction.

Steinberg provided some evidence using metacholine to stimulate nitric oxide production. They found a dose-dependent increase in blood flow in lean subjects. This response was attenuated in the obese or diabetic (Steinberg HO, et al. J Clin Invest.1996;97:2601).

“It is well recognized that you have ED with metabolic syndrome and obesity,” said Dr. Fonseca. “There are a number of studies showing that the statins may be particularly beneficial in restoring endothelial function.”

MI often occurs in patients who do not have tight stenosis. This may be related to unstable plaques that rupture leading to thrombosis and inflammation. The vulnerable plaque is very thin, lipid-rich with inflammatory cells.

“This brings us to a very important component of this syndrome—inflammation,” said Dr. Fonseca. “LDL cholesterol goes into the endothelium, interacts with macrophages and sets up an inflammatory process.”

C-reactive protein (CRP) is an index of inflammation and predictor of CAD. It is also associated with metabolic syndrome and diabetes.

Dr. Ridker and his group published a paper showing that those with low cholesterol and CRP were at the lowest risk for CAD. Those with elevated CRP had a doubling of risk. The risk quadrupled for those with high cholesterol and moderate CRP. For those with high levels in both measurements, there was a 8-fold increase in risk (Ridker PM, et al. NEJM. 2002;344:1557).

The pro-inflammatory cytokines and markers, including CRP, may also be important in the pathogenesis of diabetes. There are interesting indications that CRP production is dependent on the numbers of cytokines released from adipose tissue.

The CHEST study showed a reduction in CRP in all patients when hyperlipidemic subjects were randomized to atorvastatin, simvastatin, and pravastatin. A study by Jialal showed 20-30% reduction in CRP with all three major statins (Ansell BJ, et al. Heart Disease. 2003;5:2; Jialal I, et al. Circulation. 2001;103:1933).

“We know that patients with diabetes see a reduction in cardiac events with the statins,” he said. “Mortality is very high in patients with acute coronary syndromes when compared with angina and they should be treated more aggressively.”

The MIRACL study sheds some more light on potential medical therapy for this condition. Patients presenting with unstable angina or non—Q wave infarcts were randomized to 80 mgs of atrovastatin, usual care or placebo and followed for 4 months.

There was a decrease in LDL in the atrovastatin group to 72, which is well below the 100 target for these patients. Looking at time to first event, there was a significant reduction in death, MI, cardiac arrest, repeated hospitalizations, or revascularization. There was also a 50% reduction in stroke (Schwartz, GG, et al. JAMA.2001; 285:1711).

“Based on these studies, we now need to find out what are optimum levels,” said Dr. Fonseca. “We have some guidance from studies looking at LDL reduction to more aggressive levels.”

The Heart Protection Study (HPS) looked at patients at increased risk for CAD because of a previous MI, peripheral vascular disease, diabetes, or hypertension and total cholesterol > 135. They were randomized to 40 mgs of simvastatin or placebo independent of baseline LDL.

The simvastatin arm had significant reductions in mortality, cardiovascular death, stroke, and all major cardiovascular events. Since baseline LDLs were not incorporated in the randomization process, there was a sub-set of patients with baseline LDLs less than 100 who would probably not be treated otherwise. Even in these patients, there was a significant 21% relative risk reduction of subsequent MI (Heart Protection Study Collaborative Group. Lancet. 2002; 360:7).

Similar findings were seen in the Anglo-Scandinavian Cardiac Outcome Study (ASCOT). Ten thousand patients with hypertension and three other coronary risk factors aged 40 to 75 were enrolled. They did not have high cholesterol levels and would not normally be treated. Those receiving atrovastatin had a risk reduction of 35% in MI or congestive heart failure when compared with placebo (Sever PS, et al. Lancet. 2003;361:1149).

“The surprising finding is that it didn’t matter what your LDL baseline was,” said Dr. Fonseca. “If you are at target, you are still at risk so lowering your cholesterol further reduces the risk of MI.”

Results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) were not as robust as others and have been taken as a negative trial. However, what Dr. Fonseca took away was that those who are not aggressive in their treatment will not get the results seen in the HPS (ALLHAT Collaborative Research Group. JAMA. 2002;288:

“If you look at the placebo groups in 4S study, West of Scotland Coronary Prevention Study (WOSCOPS) and HPS and plot the treated groups, you get a linear regression line,” said Dr. Fonseca. “Even when you are getting cholesterol levels down to 90, there is still a reduction in the risk of subsequent MI.”

Targeting High-Risk Patients: What Tests are Best?

Current knowledge explains 50% of coronary heart disease using risk factors. There still remains a considerable amount of risk unexplained.

“We know empirically that the most potent statin reductions in the literature still don’t get the risk much below 40% beyond placebo,” said Ronald M. Krauss, MD, University of California, Berkeley. “Particularly with moderately elevated LDL at baseline, we don’t always have the tools to achieve that kind of reduction. It makes sense to look at targeting other risk factors.”

He focused on five factors that are easily measured and familiar to practitioners. These include lipoprotein-related factors such as lipoprotein-a (Lp(a)), Apo B and small dense LDL. The other two are homocysteine and C-reactive protein.

“Lp(a) is a fascinating molecule made up of an LDL particle surrounded by Apo(a) that resembles plasminogen,” he said. “It has a second bad feature as the LDL cholesterol and Apo B protein are rolled into one.”

Apo(a)’s interference with plasminogen has many effects on the artery wall ranging from fibrinogen binding to proliferation of muscle cells, lipid infiltration, and oxidative stress. There are over 35 isoforms of the molecule that do not necessarily have pathogenicity. Further confusing the situation is that elevated CAD risk is seen in some, but not all, studies.

There are currently no good ways to treat elevations in Lp(a). However, there is some evidence that Lp(a) may not be as bad for arteries as an isolated risk factor in the presence of low LDL. In those with high LDL and Lp(a) levels, it should spur more aggressive LDL lowering.

“We are waiting further scientific information on how these factors come into play,” said Dr. Krauss. “I recommend Lp(a) testing in those with a strong family history of premature coronary disease.”

Another protein marker seeing resurgence in interest is Apo B. In addition to being part of Lp(a), it is the protein present in the whole spectrum of atherogenic particles including LDL, VLDL, and intermediate density lipoproteins. Assays provide a measure of their number since there is one Apo B molecule for each particle. We do not yet have the research to establish normals or target treatments.

The Quebec Cardiovascular Study showed that Apo B above the median added significantly to the risk associated with an elevated total-to-HDL-cholesterol ratio. Numbers over 120 are a reasonable benchmark, particularly in those with elevated triglycerides or with metabolic syndrome (Lamarche E, et al. Circulation.1996;94:273).

“There are few studies, like the Apolipoprotein Mortality Risk (AMORIS) trial, suggesting the Apo B to A-1 ratio is a stronger predictor of risk than any standard lipid risk markers,” said Dr. Krauss. “Although this is not a resolved area and we have no firm guidelines for Apo B measurement, it is certainly something to consider.”

The third factor in the atherogenic lipoprotein category is LDL heterogeneities, specifically small, dense LDL. Standard LDL tests measure a composite of these components, ignoring the sub-classes.

LDL particle size studies show two subgroups of individuals. Those who have predominantly the larger molecule are known as the A-group. B-group individuals have smaller LDL molecules and a cluster of risk factors including higher triglyceride levels, lower levels of HDL, and higher levels of atherogenic remnants.

“Several prospective studies show that small, dense LDL contributes to risk,” stated Dr. Krauss. “Three were published in 1996 and 1997, all showing roughly a three-fold higher risk of CAD in individuals with a small LDL profile.”

A more recent paper from the Quebec Study shows that increased levels of small LDL particles, <255 angstroms, predict increased risk of heart disease independent of triglyceride, Apo B or LDL cholesterol. (St. Pierre AC, et al. Circulation.2001;104:2295)

Dr. Krauss sees this as an independent risk factor that trumps the standard lipid measurements. This suggests small LDL is a marker for a pathway associated with metabolic syndrome and Type-2 diabetes.

“Small LDL provides risk information that may prove most useful when standard risk assessments are borderline or inconclusive,” stated Dr. Krauss. “It can be an aid in assessing the effectiveness of treatment by indicating when you have normalized LDL particle size.”

He next turned to two non-lipid markers, C-reactive protein and homocysteine. The case for homocysteine is muddy at best with a recent meta-analysis of 30 prospective and retrospective trials concluding that elevated levels are a modest predictor at best for ischemic heart disease and stroke (The Homo-
cysteine Studies Collaboration. JAMA. 2002;288:2015).

More studies are being published showing that C-reactive Protein (CRP) is a marker for CAD. The protein is regulated by interleukin-6 (IL-6) and cytokines arising from adipose tissue as well as the endothelium. Dr. Krauss noted that interpretation of this test needs to be done cautiously since levels increase whenever there is an inflammatory response in the body.

“One of the intriguing things about C-reactive protein is its very strong relationship with adiposity and insulin resistance in the obese patient,” said Dr. Krauss. “It is also being recognized as a strong marker as lipid measurements in the metabolic syndrome.”

A statement released by the Centers for Disease Control and Prevention and the American Heart Association concluded that screening for inflammatory markers is not justified in healthy populations. However, it may be useful in making medication decisions in the ATP-III 10-20% “gray zone” (Pearson TA, et al. Circulation. 2003;107:499).

“Right now, we don’t have the answers about how these tests fit into clinical practice,” said Dr. Krauss. “I think they can help us sharpen our risk assessments and, used judiciously, help improve the risk in our patients.”

Assisting Patients in Reaching Goal: A New Therapeutic Approach

Treatment alternatives are needed for a variety of patients. Among them are those who fail to achieve LDL-C targets with statin monotherapy, have poor tolerance of current statins, have safety concerns that limit dose increases, have poor compliance with statin alternatives, are reluctant to use combination therapies, or prefer non-systemic therapy.

“As I look down this list, I can personally think of quite a few patients who meet at least one of the criteria,” said Athena Philis-Tsimikas, MD, from the Whittier Institute of Diabetes in La Jolla, CA.

Ezetimibe is the newest agent that works to inhibit sterol transportation. It localizes its action on the intestinal wall so peripheral exposure is limited, and inhibits absorption of cholesterol and the glucuronide metabolite. There is no impact on absorption of triglycerides, vitamin A, vitamin D, or other nutrients. The medication undergoes enterohepatic circulation that repeatedly delivers the agent back to site of action.

Studies show a 17% reduction in LDL, which is about the same as the resins. It lowers triglycerides and has a good safety profile (Dujovne, CA et al. Am J Cardiol. 2002;90:1092).

“Ezetimibe may have its best uses in combination therapy,” said Dr. Philis-Tsimikas.

Trials by Kosoglou and others showed simvastatin alone resulted in a 35% reduction in LDL. When you add ezetimibe, you increase the reduction by the exact amount it did on its own, making this an additive effect. There were similar additive results when combined with atrovastatin for an additional 16% reduction in LDL (Kosoglou T, et al. Atherosclerosis. 2000;151:135A; Kosoglou T, et al. J Am Coll Cardiol. 2001;37 (suppl a):229A) (Figure 1).

Another treatment option for diabetic patients with hypertriglyceridemia is fibric acid. In a small study by Kosoglou’s group, fenofibrate or ezetimibe alone lowered LDL cholesterol by 13% and 22% respectively. When combined, the results showed a nearly 36% reduction. There was also a 36% decrease in triglycerides (Kosoglou T, et al. European Atherosclerosis Society Meeting. Glasgow, Scotland. 2001).

“The ezetimibe and statin combination is more effective in lowering LDL than statin monotherapy, with a similar safety profile,” said Dr. Philis-Tsimikas. “Coadministration with a fibrate, at least in this small study, showed a 23% further reduction in LDL versus fibrate alone.”

There are two potential clinical roles for ezetimibe. One is monotherapy in those patients requiring only modest (around 17%) lowering of cholesterol or in those who cannot or will not tolerate other lipid-lowering agents. The second is in combination with other medications in those not at goal with current therapy or as an alternative to increasing the dose of other agents.

“Ezetimibe is a highly specific cholesterol absorption inhibitor that is safe, convenient and well-tolerated,” noted Dr. Philis-Tsimikas.