These educational activities, certified by accredited providers, were not prepared by Medscape's editors, but are made available

on our site as a service to our audience. Authors are routinely instructed by the provider to disclose significant financial relationships and mention of investigational drugs and unapproved indications. Medscape has received a fee for posting these activities. Direct questions or comments to: CME@webmd.net.

Dyslipidemia and Diabetes: Reducing Macrovascular Risk
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Copyright © 2005 Joslin Diabetes Center.
This CME activity "Dyslipidemia and Diabetes: Reducing Macrovascular Risk" was originally offered as a CME-accredited monograph in November 2004.

Faculty affiliations and disclosures are at the end of this activity.

Release Date: January 26, 2005; Valid for credit through January 26, 2006

Target Audience
This accredited activity has been developed for primary care physicians and other clinicians who manage people with diabetes.

Goal This activity reviews the pathophysiology of type 2 diabetes and macrovascular risk factors associated with the metabolic syndrome and identifies appropriate markers to trigger intervention in patients with the metabolic syndrome in type 2 diabetes. It presents recent trial data and recommendations for you to help your patients with diabetes achieve the new target treatment goals from the National Cholesterol Education Program. Learning Objectives Participants will be provided with evidence-based practical and clinically relevant information. At the completion of this activity, the participant should be able to: 1. Recognize people who are at risk for macrovascular disease based on the presence of components of the metabolic syndrome 2. Utilize an understanding of the interrelationships of the various components of the metabolic syndrome to design and initiate comprehensive preventive and treatment strategies aimed at reducing the risk of macrovascular disease 3. Identify patients with dyslipidemia early in its natural history due to an improved understanding of the role hyperlipidemia can play in the development of macrovascular disease, particularly in people with type 2 diabetes 4. Design, implement, and manage effective treatments for dyslipidemias in people with diabetes and the metabolic syndrome Credits Available

Physicians - up to 1.25 AMA PRA Category 1 continuing physician education credits
All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Participants should claim only the number of hours actually spent in completing the educational activity.

Accreditation Statements
For Physicians

The Joslin Diabetes Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Joslin Diabetes Center designates this educational activity for a maximum of 1.25 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity: cme@joslin.harvard.edu. For technical assistance, contact CME@webmd.net. Instructions for Participation and Credit There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. Follow these steps to earn CME/CE credit: 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. Medscape encourages you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 5 years; at any point within this time period you can print out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage. The credit that you receive is based on your user profile.

This activity is supported by an unrestricted educational grant from Pfizer Inc.

Legal Disclaimer The materials presented here do not necessarily reflect the views of Medscape, Joslin Diabetes Center, the companies providing educational grants or the authors and writers. These materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. All readers and continuing education participants should verify all information and consult a qualified healthcare professional before treating patients or utilizing any therapeutic product discussed in this educational activity.

Contents of This CME Activity
1. Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD A Growing Epidemic Diabetes and Cardiovascular Risk Factors that Contribute to Increased Risk of Cardiovascular Disease Type 2 Diabetes as a Risk Equivalent Defining the Metabolic Syndrome Other Definitions of the Metabolic Syndrome Prevalence and Impact of the Metabolic Syndrome Dyslipidemia in Diabetes The Vascular Injury in Patients With Diabetes The Impact of Multifactorial Intervention Current Risk-Reduction Strategies 2. Dyslipidemia: Etiology and Treatment Strategies Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Characterizing Dyslipidemia in Type 2 Diabetes and the Metabolic Syndrome How Blood Pressure and Glycemia Relate to Cardiovascular Disease and Microvascular Complications Current Control of Risk Factors Statin Therapy in Patients With Diabetes Cholesterol-Lowering Goals in Patients With Diabetes Benefits of Statin Therapy Use of Other Lipid-Lowering Agents Combination Therapy for Lipid Lowering Background on the CARDS Trial Summary of CARDS Findings Going Beyond Conventional LDL Goals Other Continuing Trials in Aggressive Lipid-Lowering Therapy 3. Joslin Diabetes Center Guidelines for Screening and Management of Dyslipidemia Associated with Diabetes Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD 4. References

Dyslipidemia and Diabetes: Reducing Macrovascular Risk

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD A Growing Epidemic

Table 1. Countries with Highest Number of Estimated Cases of Diabetes (in millions) for 2000 and 2030
All evidence indicates that we are currently in the middle of a global diabetes epidemic. In fact, type 2 diabetes is being diagnosed with increasing frequency in children and adolescents, and in some parts of the world may be more common than type 1 diabetes.[1] As an illustration of this global increase, according to the World Health Organization (WHO), in the year 2000 there were 177 million people diagnosed with diabetes around the world, and by year 2030, that number will grow to 366 million (Table 1). [2] The problem is particularly serious in countries like India and China, where resources to care for this growing number of people with diabetes are scarce. Currently, the US has the third largest number of cases, with an estimated 18 million people with diabetes. In addition, there are more than 50 million people with metabolic syndrome or insulin resistance syndrome, which is the pool of people at high risk for developing type 2 diabetes.[2] One of the major reasons for the increasing prevalence of diabetes and its precursors such as prediabetes or metabolic syndrome is the increasing rate of obesity. In the United States, more than 60% of the adult population is currently overweight, defined by body mass index (BMI) of 25, and about 30% are obese, defined by BMI of about 30. [3] As diabetes develops so does heart disease. While it is important to prevent diabetes, it has also become essential to develop strategies for minimizing the risk of cardiovascular complications in people already diagnosed with diabetes.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Diabetes and Cardiovascular Risk
Macrovascular disease including coronary artery disease and other vascular events such as stroke and peripheral vascular disease is responsible for nearly 80% of all diabetes mortality, while 75% of all hospitalizations in diabetes patients is due to cardiovascular events.[4] Furthermore, because new-onset diabetes often does not cause any symptoms for many years, 1 out of 3 people with diabetes remains undiagnosed, even in developed countries such as the United States. [2,4] Therefore, it is not surprising that a third of patients already have cardiovascular disease (CVD) by the time they are diagnosed with diabetes. Epidemiologic studies such as the Framingham Heart Study reveal the impact of diabetes on cardiovascular events. A 30-year follow-up of subjects in that study found an increase in the prevalence of complications such as coronary heart disease, cardiac failure, intermittent claudication, and stroke in patients with diabetes, compared with corresponding nondiabetic men and women in the age range of 35 to 64 years. Women with diabetes showed a relatively greater increase in the risk of cardiovascular events than women without diabetes.[5]

Figure 1. Cardiovascular mortality in type 2 diabetic patients vs nondiabetic cohort.
A study by Krolewski and colleagues compared the long-term follow-up status of the Joslin Diabetes Center patient population with the nondiabetic Framingham Heart Study population. This comparison revealed a 2-fold greater incidence of mortality from cardiovascular disease in the cohort of men, and a 4- to 5-fold greater mortality from cardiovascular disease in women with diabetes (Figure 1). [6] This was surprising because the absolute rate of cardiovascular disease in nondiabetic women is considerably lower than that in nondiabetic men. A comparison of the National Health and Nutrition Examination Survey (NHANES) data from 1982 to 1984 vs that of 1971 to 1975 revealed that coronary artery disease mortality actually decreased by 36% and 27% in the nondiabetic men and women, respectively. However, the decrease in the cardiovascular mortality among men with diabetes was not nearly as great, and in women with diabetes, there was actually some increase.[7] These data raise some questions: What are the factors that increase the risk of coronary heart disease mortality in people with diabetes? Secondly, what can be done to prevent the marked increases in cardiovascular events in both men and women with diabetes? An analysis of the Multiple Risk Factor Intervention Trial (MRFIT), which enrolled more than 350,000 men at its outset, including more than 5000 with diabetes, demonstrated that the risk in the diabetic population for death from cardiovascular disease was several-fold greater for those with any 1, 2, or all 3 of these risk factors: Total cholesterol above 200 mg/dL, smoking, and systolic blood pressure greater than 120 mm Hg. [8] These findings suggest the need for more intensive risk factor management in people with diabetes, because their vasculature may be more susceptible to the effects of elevated cholesterol, high blood pressure, smoking, and other risk factors. Similarly, mean blood pressure of 144/82 mm Hg compared to 154/87 mm Hg in the United Kingdom Prospective Diabetes Study (UKPDS) resulted in major benefits in cardiovascular endpoints.[9]

Figure 2. Incidence of myocardial infarction in people with type 2 diabetes.
The incidence of myocardial infarction (MI) in people with diabetes was compared with that of nondiabetics. After 7 years of follow-up, the people without diabetes had an MI rate of about 3.5%. In those with diabetes, the risk of developing a first MI was the same as that of nondiabetics who had a previous MI (Figure 2). [ 10] This study also demonstrated that in people with type 2 diabetes who had a previous MI, the risk of having a second MI in the next 7 years was as high as 45%.[10] This study has led to the notion that diabetes is a cardiovascular risk equivalent, which implies that people with diabetes are considered at the same high risk for a cardiovascular event as people without diabetes but a prior cardiovascular event.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Factors that Contribute to Increased Risk of Cardiovascular Disease

Table 2. Factors Underlying Accelerated Atherogenesis In Diabetes
What are some of the reasons for this accelerated course of atherosclerosis and marked atherogenesis in patients with diabetes? (Table 2). Among the many factors involved, an important one is dyslipidemia. In addition to elevated low-density lipoprotein (LDL) cholesterol that is prevalent in the general population, patients with type 2 diabetes have specific lipid

abnormalities, including triglyceride-rich lipoproteins, low levels of high-density lipoprotein (HDL) cholesterol, and a compositional change in the LDL -- smaller, denser LDL particles, which are more atherogenic. Additional mechanisms include hyperglycemia, resulting in multiple, intermediary pathways, increased oxidative stress, endothelial dysfunction, hematological abnormalities leading to a procoagulant state, as well as hypertension and perhaps insulin resistance itself.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Type 2 Diabetes as a Risk Equivalent
Evidence for increased risk of cardiovascular disease in people with diabetes led the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP) to label type 2 diabetes as a coronary heart disease (CHD) risk-equivalent in 2001. The 10-year risk of CHD in patients with diabetes is considered to be greater than 20%, which defines the CHD risk-equivalence, according to ATP III. [11]

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Defining the Metabolic Syndrome
Metabolic syndrome is a diagnosis that has been in evolution. In 1988, Dr. Gerald Reaven coined the term "Syndrome X" to describe a cluster of abnormalities including glucose intolerance, hyperinsulinemia, elevated triglycerides, low HDL, and hypertension. [12] Each of these markers is considered a risk factor for coronary artery disease. Since these factors may work in synergy in people with this syndrome, it is expected that these individuals are at increased risk of coronary artery disease. Often concomitant with Syndrome X, which is currently called the metabolic syndrome, is central obesity. Central obesity is an excessive deposition of fat in the abdominal area. It is associated with insulin resistance. Some studies have indicated that the greater the abdominal visceral adiposity, the lower the glucose disposal. [13]

Table 3. ATP III Definition of the Metabolic Syndrome
As mentioned earlier, a large number of people in the United States are considered to have the metabolic syndrome, which can precede type 2 diabetes. This may also result in coronary artery disease even in people who never go on to develop type 2 diabetes. The guidelines released by the NCEP ATP III provide one way to define the metabolic syndrome [11] (Table

3). These guidelines suggest examining 5 clinical parameters: Abdominal obesity (defined by waist circumference), triglycerides greater than 150 mg/dL, low HDL cholesterol, blood pressure of greater than 130/85 mm Hg, and any fasting glucose that is above the normal of 110 mg/dL or less.[11] (Note that the American Diabetes Association recently redefined normal fasting sugar level as 100 mg/dL or less.[14] ) The presence of any 3 of these 5 factors defines the diagnosis of the metabolic syndrome.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Other Definitions of the Metabolic Syndrome
The WHO has defined the metabolic syndrome slightly differently than the ATP III definition cited above. WHO stipulates that impaired glucose tolerance, impaired fasting glucose, diabetes, or any evidence of insulin resistance must be present in order to diagnose this disorder. In addition, any 2 of these remaining 4 risk factors must also be present: Abdominal obesity (defined by BMI rather than waist circumference), dyslipidemia, blood pressure of 140/90 mm Hg or greater (different from the ATP III cutoff), and microalbuminuria (not included in the ATP III guidelines). [15] The American Association of Clinical Endocrinologists (AACE) uses still another definition. The AACE criteria are based on whether the patient has any risk factors that suggest insulin resistance (such as high BMI, sedentary lifestyle, age above 40 years, membership in a minority population, family history of diabetes, history of gestational diabetes) and any 2 parameters from a list similar to that of the ATP III guidelines, [16] but it includes a 2-hour post-glucose load level of greater than or equal to 140 mg/dL. The similarities among these definitions are more important than the differences. The key point is that the metabolic syndrome increases macrovascular risk, and must be addressed clinically to reduce the incidence of vascular disease.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Prevalence and Impact of the Metabolic Syndrome
Twenty five percent of adults in the United States aged 20 to 79 years have the metabolic syndrome as defined by the NCEP, while in people above the age of 50 years, 40% to 45% or more may have it. There are also ethnic differences in the distribution of the metabolic syndrome. Type 2 diabetes is more common in all other ethnic populations when compared to white populations, and the metabolic syndrome follows the same pattern. In fact, the highest prevalence of the metabolic syndrome is in Mexican American men and Mexican American women, according to recently published data from the Centers for Disease Control and Prevention.[17] Metabolic syndrome frequently precedes the development of diabetes, and it is also a risk factor for heart disease. An important longitudinal study of the large Mexican American population of the city of San Antonio compared people over 8 years of age who remained nondiabetic to those who went on to develop diabetes. The individuals who eventually developed diabetes were those who had slightly more central abdominal fat, higher triglycerides, lower HDL cholesterol, and higher systolic blood pressure. They also statistically had significantly elevated fasting glucose at baseline. Their fasting insulin levels were also about twice as much, meaning that these individuals had insulin resistance.[18] Additional data from the San Antonio Heart Study revealed that as insulin sensitivity decreased, HDL cholesterol decreased progressively, triglycerides increased, and both systolic and diastolic blood pressure increased.[18,19]

Figure 3. Elevated risk of CVD prior to clinical diagnosis of type 2 diabetes.
These data are supported by recent 20-year prospective analyses of the Nurses' Health Study. In this very large population it was shown that the risk of cardiovascular disease indeed occurred prior to the clinical diagnosis of type 2 diabetes [20] (Figure 3). In Figure 3, the women who remained nondiabetic throughout the study were assigned a relative risk of developing heart disease of 1. For those who received a diagnosis of diabetes after entry into the study, the relative risk for developing heart disease was 3.5 to 4. The risk for those who had diabetes at baseline was 5. However, even those women who had not yet been diagnosed with diabetes were having cardiovascular events at a 2.8-fold higher rate than those who remained nondiabetic throughout the study.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Dyslipidemia in Diabetes
Dyslipidemia in diabetes typically consists of lipid abnormalities that arise years before the diagnosis of diabetes. Whether a person has diabetes, metabolic syndrome, or insulin resistance, they tend to have higher triglycerides, increased very low density lipoprotein (VLDL), and higher levels of small, dense LDL, with or without some increase in the LDL, while the HDL is usually low. The prevalence of dyslipidemia is greater among patients with diabetes, particularly women. An analysis of the second NHANES (NHANES II) revealed that women with diabetes had twice the prevalence of lipid abnormalities as nondiabetic women. In addition, a fairly significant proportion of both men and women with diabetes had lower HDL and more elevated triglycerides than those who did not have diabetes.[21] Furthermore, in MRFIT, when the age-adjusted cardiovascular disease death rate in patients with type 2 diabetes was examined according to the levels of total cholesterol, there was a considerable increase, even among patients with mild elevations (eg, at less than 180 mg/dL of total cholesterol, equivalent to an LDL of 100 to 110 mg/dL). A similar examination of the relationship between elevated blood pressure and cardiovascular disease mortality showed that not only was the risk obviously higher in people with high blood pressure, but people with diabetes who have systolic blood pressure between 120 and 160 mm Hg have a greater than 2-fold higher risk of mortality.[8] This reaffirms the increased susceptibility of the vasculature at each increment of blood pressure.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD The Vascular Injury in Patients With Diabetes
We still are attempting to understand the many factors that contribute to the accentuation of atherogenesis in diabetes. Receiving a great deal of attention are the early events leading to the formation of advanced glycosylation end products and the consequences of these end products, as well as subclinical inflammation. All of these factors result in oxidative stress, which in turn results in subtle changes in the endothelium at the cellular level, leading to atherogenesis. In addition, current research shows that nitric oxide synthesis is reduced in the presence of increased oxidative stress. It is also known that angiotensin II is involved in perpetuating this process. Currently, there is considerable debate as to whether C-reactive protein (CRP) should be measured as a marker of subclinical endothelial inflammation. CRP is almost always increased in patients with type 2 diabetes, and may even precede the diagnosis. Data from such trials as the Women's Health Study indicate that subclinical inflammation does correlate with the increased risk of cardiovascular events. In that study, women with a normal CRP but documented metabolic syndrome or those with high CRP and no metabolic syndrome both had a decrease in risk-free survival relative to women who had neither the metabolic syndrome nor a high CRP level. Moreover, women with both the metabolic syndrome and a high CRP had the worst prognosis for cardiovascular disease. [22] There may be some situations--particularly in those patients who are in the intermediate risk category such as those with 10-year CHD risk at 10%-20% according to ATP III guidelines [23] --where measurement of CRP may be helpful, particularly in the nondiabetic population or prediabetic population. Since the level of CRP increases according to a number of metabolic syndrome risk factors,[24] a high CRP may be a good indicator of metabolic risk due to endothelial injury. An analysis of data from the Framingham Heart Study confirmed that CRP can serve a role as a prognostic marker. [25] In addition, recent studies have reported a decrease in CRP levels with statin treatment, and a greater decrease with higher doses of certain statins [26-28] although the clinical implications of this finding are unclear.

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD The Impact of Multifactorial Intervention
The Steno-2 trial (from the Steno Diabetes Center in Denmark) was a multifactorial intervention in people with type 2 diabetes that examined the effects of a comprehensive approach to managing multiple risk factors in these patients. This study followed 160 subjects with microalbuminuria over 8 years to examine the impact of 2 interventions. All patients received behavior modification, whereas only one group received, in addition, much more aggressive intervention for glycemic control, hypertension, dyslipidemia, and microalbuminuria. [29] The intensive therapy consisted of better diet, a practical exercise strategy, and smoking cessation. Glycemic control was attempted with oral agents and/or insulin as needed. For management of hypertension, a number of agents, including diuretics, angiotensin converting enzyme inhibitors (ACE-I), calcium channel blockers, and beta blockers were prescribed as needed. Statins and fibrates were used as needed to achieve good control of both LDL and triglyceride abnormalities.[29]

Figure 4. Steno-2: multifactorial intervention and CVD in type 2 diabetes: impact on risk factors.
This long-term study demonstrates how difficult it is to achieve the desirable goals of glycemic management. Even after comprehensive, intensive therapy and motivation, less than 20% of the subjects achieved normal hemoglobin HbA 1c (A1C) concentrations less than 6.5% (Figure 4). About 70% of the patients in the intensive therapy group were able to achieve a significant improvement in total cholesterol level, but triglyceride differences between the 2 groups were not significant. [29] The systolic blood pressure goal of less than 130 mm Hg was achieved in about twice as many people in the intensive therapy group. Diastolic blood pressure, which is somewhat easier to control, was well controlled in both groups. [29]

Figure 5. Steno-2: multifactorial intervention and CVD in type 2 diabetes: impact on end points.
Although success was less than perfect in the reduction of risk factors, the risk factor improvement was certainly better in the intensive therapy group. With this comprehensive approach, a 53% reduction in the combined endpoints of cardiovascular disease was seen, including mortality from cardiovascular disease, nonfatal MI, coronary artery bypass grafting (CABG) surgery, revascularization with stents, nonfatal stroke, amputation, and surgery for peripheral artery disease[29] (Figure 5). In addition, there were major reductions in nephropathy, retinopathy, and autonomic neuropathy. This led the authors to conclude that a targeted, long-term, intensified intervention aimed at reducing multiple risk factors decreases quite significantly the risk of both cardiovascular and macrovascular endpoints.[29]

Diabetes, the Metabolic Syndrome, and Vascular Health: Clinical Interrelationships
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Current Risk-Reduction Strategies
The Steno-2 study and other evidence-based strategies support current treatment recommendations, which are: The A1C goal for all patients should be less than 7%, and even lower if possible. The LDL goal for all patients with diabetes is less than 100 mg/dL, and LDL less than 70 mg/dL is a therapeutic option in patients at very high risk (eg, who have type 2 diabetes plus coronary heart disease or other risk factors). The goal for blood pressure should be less than 130/80 mm Hg. Aspirin should be administered to all adult patients, unless contraindicated. ACE-I or angiotensin II receptor blocker (ARB) should be a part of the therapeutic regimen for people with diabetes who have albuminuria or are above age 55 years, and have 1 additional risk factor; this is based on the results of the Heart Outcomes Prevention Evaluation (HOPE) study.[30] Beta-blockers should be prescribed for patients with concomitant diabetes and coronary artery disease. For reducing mortality, the benefits outweigh the risks of these agents.[31] Unfortunately, despite the availability of these proven strategies, the vast majority of patients with diabetes all over the world (including the United States) are not reaching recommended goals. Greater awareness of the need to reach those goals and further dissemination of proven strategies should lead to better patient outcomes over the long run. It is important to note that any reduction in A1C, lipids, and blood pressure benefits patients with diabetes even if they do not reach these goals.[31,32]

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Characterizing Dyslipidemia in Type 2 Diabetes and the Metabolic Syndrome

Figure 6. Vascular effects of risk factors: elevated LDL-C plays key role in disease progression.
Considerable data have accrued suggesting a key role for low-density lipoprotein (LDL) in determining vascular risk, and it plays this role at multiple stages of the disease. During the initiation phase, LDL contributes to the development of the atherogenic plaque. During the

progression phase, the Glagov hypothesis suggests that as the lipid core becomes much larger, outward remodeling occurs. The crucial stage, in terms of coronary events, is plaque rupture, and the risk of rupture is believed to be enhanced by a large lipid core [33] (Figure 6). In addition, there is evidence that modifications of lipoproteins, particularly LDL, enhance their uptake in macrophages, in the production of foam cells.[9] So what characterizes dyslipidemia in type 2 diabetes and the metabolic syndrome? The previous section underscored that elevated triglycerides and average LDL cholesterol levels occur in most people with type 2 diabetes and noted that the composition of the lipoproteins changes so the particles are smaller, denser, and more atherogenic. [35] A direct measurement of the number of particles, such as of an apolipoprotein B (APO-B), reveals that this number is increased. Some groups, such as the Canadian advisory group, now suggest measuring APO-B as well as LDL cholesterol in some patients. [36] In addition, there are clearly increases in chylomicrons in very low density lipoproteins. When these are acted upon by lipoprotein lipase, they form remnants, are atherogenic, and have low highdensity lipoprotein (HDL). [37] These changes occur not only with type 2 diabetes, but also in people with the metabolic syndrome and prediabetes. Non-HDL cholesterol, which has recently been identified as a secondary target by the National Cholesterol Education Program, Adult Treatment Panel III (NCEP, ATP III, [11] is also elevated in type 2 diabetes.

Figure 7. Glucose intolerance increases risk for dyslipidemia/hypertension: Botnia study.
The Botnia study, performed in Finland, looks at dyslipidemia (Figure 7), defined in this case as high triglycerides and/or low HDL. This study reveals that the lipid abnormalities are relatively more severe in people with type 2 diabetes when they are present, and at intermediate levels for people with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), relative to subjects with normal glucose tolerance. It also shows that not only are lipid abnormalities present when there is IFG and IGT, but also increased blood pressure. [38] As discussed, the LDL cholesterol goals in both the NCEP and American Diabetes Association (ADA) are less than 100 mg/dL. This means that LDL is treated to the same degree of intensity in people with diabetes as in people with cardiovascular disease. This is based on meeting 3 criteria:

1. The risk of vascular disease in diabetic subjects without pre-existing vascular disease
is similar to that in nondiabetic subjects with pre-existing vascular disease.

2. Intensive glycemic control alone will not completely eliminate the excess risk of
coronary heart disease (CVD). This is important because, in fact, glycemic control has some effect on CVD risk, but the slope of the line is not sufficiently great that glycemic control alone can be the goal.

3. The evidence is now overwhelming that lipid and blood pressure interventions to
reduce coronary heart disease are equally effective in subjects with and without diabetes.

Dyslipidemia: Etiology and Treatment Strategies

Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD How Blood Pressure and Glycemia Relate to Cardiovascular Disease and Microvascular Complications

Figure 8. MI and microvascular end points: incidence by mean systolic BP and A1C concentration.
Data from the United Kingdom Prospective Diabetes Study (UKPDS) show some similarities in the effects of blood pressure and glucose control on microvascular and macrovascular disease[9,32] (Figure 8). The left side of Figure 8 shows the average systolic blood pressure over 10 years. The green line is myocardial infarction (MI), and the red line is microvascular disease. Note that these 2 lines are parallel, meaning the effect of systolic blood pressure on microvascular and macrovascular disease is similar. Secondly, MIs are more common than microvascular events in newly diagnosed patients with diabetes. A third point that is relevant to the establishment of treatment guidelines is that there is no evidence that at very low blood pressures there might be an increased risk of complications. In all studies in subjects with diabetes, both microvascular and macrovascular disease declined with lower blood pressure. This is an important issue because the Hypertension Optimal Treatment (HOT) trial, a randomized controlled trial, justifies diastolic blood pressure goals of less than 80 mm Hg without corresponding evidence for a 130 mm Hg systolic goal. [39] The UKPDS tests in a randomized design the effects of a systolic blood pressure of 145 mm Hg vs 155 mm Hg. [40] So the currently recommended systolic goal of less than 130 mm Hg is a compromise, halfway between the implications of the clinical trial data and those of the epidemiologic data. The chart on the right side of Figure 8 reflects the effect of A1C levels on event rates and covers a large range from 5.5% to 11%. It demonstrates that the risk of MI doubles from one extreme to another, showing that A1C is related to CHD. However, if we calculate the size of the effect, each 1% change in A1C is equivalent to about a 15% rise in risk of MI. Therefore, even if you bring someone's A1C level down from 10% to 6%, it is unlikely you will fully eliminate the 2- to 4-fold excess of cardiovascular disease in people with diabetes. On the other hand, a 15% change per 1% A1C is not trivial. A 2% change in A1C would reduce risk 30%, an effect similar to that seen in statin trials. [41] Therefore, it makes sense to use both approaches -- glucose and lipid control -- in at-risk people. Another reason to further examine the chart on the right side of Figure 8 is to understand why the slope is relatively gentle, reflecting modest impact of A1C on event risk. A possible explanation is that there is already increased risk of cardiovascular disease prior to the onset of type 2 diabetes. The increased triglycerides, decreased HDL, increased systolic blood pressure, and increased glucose and insulin levels that these patients have are all components seen in the various definitions of the metabolic syndrome, thus combining their effects to increase macrovascular risk beyond that which relates to A1C alone.

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD

Current Control of Risk Factors

Figure 9. Risk factor control in adults with diabetes: NHANES III (1988-1994)/NHANES (1999-2000)
A recent paper in the Journal of the American Medical Association (JAMA) compared what has been happening over time to control of risk factors in subjects with diabetes (Figure 9). In this figure, the red bars represent National Health and Nutrition Examination Survey (NHANES) III (1988-1994). What this shows is that, while blood pressure, total cholesterol, and total glucose control have all improved, A1C control has actually deteriorated.[42] Clearly, given these percentages, we are still a very long way from having most of our people with diabetes under control. This is especially true since less than half of these people have adequate cholesterol control, even though a LDL cholesterol level of 100 mg/dL can be achieved by statins alone.

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Statin Therapy in Patients With Diabetes
How effective are statins in the overall population and in people with diabetes? Generally, the evidence from major coronary heart disease primary prevention trials such as the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) and secondary prevention trials such as Cholesterol and Recurrent Events (CARE), the Scandinavian Simvastatin Survival Study (4S), and Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) show that coronary heart disease reduction in the overall population is paralleled in people with diabetes,[43-47] although the data for secondary prevention are more impressive than that for primary prevention. The Heart Protection Study (HPS) included about 6000 people with type 2 diabetes and examined the effects of simvastatin vs placebo on 5-year rates of first major vascular event. Patients in this study could enroll either with arterial disease and diabetes, occlusive arterial disease alone, or diabetes alone. [48] HPS also showed that the effectiveness of statins at reducing cardiovascular events was the same in people with diabetes who had either an LDL cholesterol below 116 mg/dL or above 116 mg/dL. HPS was half secondary and half primary prevention, and the data by LDL cholesterol have not been broken out for the diabetic primary prevention population. There was also an analysis of people with type 1 diabetes in this study. About 600 people had type 1 diabetes, and, although the results were not statistically significant, they showed the same benefit as in the people with type 2 diabetes.[48]

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Cholesterol-Lowering Goals in Patients With Diabetes

The 2 major sets of recommendations for managing dyslipidemia that clinicians in the United States follow are those of the NCEP and the ADA. [11,49] In both of these sets of recommendations, lowering LDL cholesterol is the primary goal, and the LDL goal is less than 100 mg/dL. Recently, the ADA goals have been revised to suggest that all patients with diabetes should be treated to less than 100 mg/dL,[14] and the American College of Physicians has recommended that all patients with diabetes should be treated with statins. [50] This is evidence of considerable evolution recently.

Table 4. NCEP ATP III and ADA: Treatment Goals in Patients With Diabetes
Table 4 compares the ADA and the NCEP recommendations, showing how the primary targets are the same. For the NCEP, non-HDL cholesterol (total cholesterol minus HDL cholesterol) is a secondary target; whereas for the ADA it is HDL and then triglycerides. Thus, there are really more similarities than differences in these guidelines.

Table 5. ADA: Treatment Recommendations
To achieve these goals, the ADA recommends lifestyle interventions plus statins (Table 5). Other drugs are discussed, including:[49] Resins, which are not commonly in use both because of their marked side effects and because they raise triglyceride levels Cholesterol absorption inhibitors such as ezetimibe are effective but not as potent as statins in lowering LDL cholesterol Niacin, an agent that has shown an appreciable ability to lower LDL but can worsen glucose tolerance Fenofibrate, a drug that appears to have only a very modest effect in reducing LDL cholesterol levels (5% to 6%) There is no question that raising HDL is difficult, and the most effective options for this

clearly are nicotinic acid and fibric acids; they are discussed in more detail later. When it comes to reducing triglycerides, the ADA strongly recommends lifestyle interventions. Weight loss and increased physical activity can be a very effective approach. Further, for patients with poorly controlled diabetes, significant improvement in glycemic control can sometimes have a considerable effect on triglycerides. Treatment with fibric acid derivatives such as fenofibrate or gemfibrozil is also very useful. Note that gemfibrozil increases risk of myositis in people on statins and niacin. Fenofibrate would be preferable if fibric acid and statins are used together. High-dose statins may also be effective in lowering triglyceride levels.[49] Not shown in Table 5, because it is not in the ADA guidelines, but still useful in lowering high triglyceride levels, are fish oils. Lowering of LDL is the primary goal of the NCEP. This group, too, recommends statins as the first choice therapy, with bile acid sequestrants or nicotinic acid the second choice (this predated the use of ezetimibe). The secondary goal is lowering non-HDL cholesterol; it becomes a target if the triglycerides are 200 mg/dL or higher. In the past, the NCEP recommended a high-carbohydrate, low-fat diet for people with insulin resistance, but they have since modified those recommendations to suggest a fat intake of between 25% and 35% of total calories. They also suggest weight reduction for the obese-and almost all patients with diabetes are--and increased physical activity. [11]

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Benefits of Statin Therapy
Statin therapy inhibits cholesterol synthesis and increases LDL receptors. These agents are the most effective available to lower LDL, although the amount of LDL lowering differs markedly among the statins. [51] The amount of HDL-raising achieved by this class is generally modest, but they differ in their effect. Meanwhile, the amount of triglyceride lowering also differs among statins and, importantly, it is much greater in people who start with higher levels of triglycerides. In clinical trials, statins have been shown to offer up to a 40% reduction in coronary heart disease and stroke. This effect appears to be attributable mainly to differences in LDL levels. There has been considerable discussion of the pleiotropic effects of statins, although some think that the idea that these medications have multiple effects has been overemphasized. There is some evidence that statins improve endothelial function, have anti-inflammatory effects, enhance plaque stability, and attenuate vascular smooth muscle cell proliferation. [52] While there has been much discussion of this over the last 5 years, more data need to be collected on these issues to confirm such speculation. There are adverse effects of statins, the most significant of which include:[53]

Myalgia (muscle pains), which is seen in about 2% to 4% of patients Myopathy including rhabdomyolysis (very rare: Incidence = 0.5-1 in 10,000 patients) Increased values on liver function tests (LFTs)
Contraindications to statin therapy include liver disease, defined by the US Food and Drug Administration (FDA) as a repeated finding of 3-fold higher LFT levels than the upper limits of normal. The potential for hepatotoxicity and the need to monitor LFTs is one of the major limitations of statin therapy. Usually with placebo the incidence of FDA-defined liver function abnormalities is 0.2% to 0.3%; it can be seen in up to 1% of individuals on statin therapy, rising with the highest doses of statins, which, in some cases, can result in significant LFT elevations in 2% or 2.5% of people on statins. [53] Myopathy is generally defined as a creatine kinase greater than 10-fold the upper limit of normal. Creatine kinase should be measured at initiation of statin therapy to determine the patient's baseline value. It is not useful to follow creatine kinase levels during therapy, because they do not predict who will ultimately develop myopathy. Myopathy occurs in about 1 in every 1000 subjects at baseline levels of statins (pravastain 40 mg, simvastatin 20 mg, or atorvastatin 10 mg). Rhabdomyolysis is said to occur in less than 1 of every 10,000 people on statins. [53] The actual risk is lower for people who do not have renal disease, or for those not using a combination of statins and fibric acids. The risk of myopathy may increase with dose escalation. It also clearly occurs when statins are used in combination with fibric acid, so in such instances it is important to weigh treatment risks against anticipated benefits. Remember that when a statin is used in combination with a fibric acid, the fibric acid should be fenofibrate, and this combined treatment should be utilized with caution in people with renal insufficiency. Niacin in combination with statins appears to have a much lower risk of myopathy. In nearly all cases,

myopathy is reversed after discontinuation of the statin or fibric acid. [53]

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Use of Other Lipid-Lowering Agents
Ezetimibe is a newer agent that blocks cholesterol absorption. Studies show that, when used as monotherapy, this agent lowers LDL by about 18%. It is mainly used in combination with statins, and it has been suggested that it is equivalent to a 3-dose titration of statins (statin 10 mg to 80 mg). Particularly with higher doses, the effect may be somewhat less, maybe a 2-fold dose elevation. This agent causes some decrease in triglycerides (unlike resins, which raise triglycerides), and a very small increase in HDL is seen.[54] This agent has very few side effects; however, there currently are no long-term safety data on mono- or combination therapy with ezetimibe although a large-scale clinical trial in renal failure (n = 9000) is currently underway. Fibric acids (including gemfibrozil and fenofibrate) are mainly indicated for treatment of elevated triglycerides. Fibric acids are known to increase peripheral lipolysis and decrease hepatic triglyceride production. They also have a peroxisome proliferator-activated receptor (PPAR)-alpha mechanism. These agents are very effective in lowering triglycerides by 25% to 50%. They are actually more effective in lowering triglycerides than is nicotinic acid, although they are less effective at raising HDL.[55] Use of fenofibrate generally does not increase LDL. It may remain stable or drop by 5% to 10%. Adverse effects include gastrointestinal upset (8%), cholelithiasis, myositis, and abnormal LFTs. Gemfibrozil is not used as often, even though most of the available clinical trial data are actually with gemfibrozil. In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), there was a 24% reduction in the primary endpoint of fatal and nonfatal coronary heart disease in patients taking gemfibrozil. [56] Note that, although this study was in people with very low LDLs and HDLs, these results were not necessarily better than those of other studies, eg High-Risk Patients with Statins (HPS), or Collaborative Atorvastatin Diabetes Study (CARDS), discussed later in this document. Nicotinic acid is probably the most controversial cholesterol-lowering drug. It is available both in immediate release and extended release. The dose range has been truncated for extended release (maximum 2 g/day), but is often not difficult to tolerate at this dose. In terms of potency it is the best agent for raising HDL-C. However, it is widely recognized to have many side effects, such as increases in LFT values, particularly the sustained release formulation. This is why it is contraindicated in patients with active liver disease or unexplained LFT elevations. Note that nicotinic acid worsens insulin resistance and increases hyperglycemia. However, it can be used in patients with diabetes if they are relatively well controlled and monitor their glucose carefully. In some patients, the benefit of this therapy may outweigh the risks.

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Combination Therapy for Lipid Lowering
Combination therapy can dramatically improve the lipid profile, and its usage has therefore increased. This approach may result in a greater lowering of LDL than monotherapy (particularly when a statin is combined with nicotinic acid). Niacin can effectively lower lipoprotein(a) (Lp(a)); however, it is important to remember that patients with diabetes do not have particularly high LP(a) levels unless they have renal failure. In fact, patients with type 2 diabetes may even have somewhat lower Lp(a) levels than nondiabetic subjects. Using niacin in combination with a statin can significantly improve (increase) particle size, an effect not usually seen with statin therapy alone. Niacin in conjunction with statins can also decrease fibrinogen levels. The benefit of treatment with fibric acid derivatives in combination with statins, as opposed to monotherapy, is also demonstrated by angiography studies and other data. The downside of combination therapy includes cost and complexity. While many physicians worry about the risk of myositis, the risk is overestimated. Even in relatively low-risk patients, however, drug interactions are a possibility. There are no outcome data on use of combination therapy. The ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is enrolling 10,000 participants at 70 clinical centers in the United States and Canada to compare the effects of intensive glycemic control

and intensive blood pressure control on major cardiovascular-related events. This study includes an arm that will assess intensive lipid control (including combination therapy) in 5800 of the participants. [57] This may help to resolve some of these issues, although the data are unavailable at the time of the present writing. This study is discussed later in this document.

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Background on the CARDS Trial
The CARDS trial, which was presented at the 64th Annual ADA meeting in June 2004 has now been published in The Lancet.[58] This study was performed only in people with type 2 diabetes, making it the first study exclusively performed in people with this condition. This was a primary prevention population, with subjects having at study entry no history of previous MI or coronary heart disease, and LDLs less than 160 mg/dL. The median LDL was in fact 120 mg/dL, which is lower than in the general population.[58] Subjects also had to have at least 1 other cardiovascular risk factor. It is likely that about 80% of subjects had the metabolic syndrome. Subjects numbering 2830 were to be followed until either 304 primary cardiovascular events occurred or 4 years of double-blind treatment was completed, whichever came first. The study was stopped about 2 years early because of highly significant findings, but the median follow-up was still 3.9 years. [58} At baseline, about a third of the people were women, and the average age was 61 years. The average body mass index (BMI) was 28.8. The study was performed in the United Kingdom.[58] This BMI would have been considered obese for that population, but less obese than in a typical American population. (The average BMI among non-Asian US diabetic subjects is about 31). The baseline LDL averaged 118 and 119 mg/dL for placebo and atorvastatin groups, respectively. In both groups, 25% of the people had LDLs below 100, and 25% had LDLs above 137 mg/dL. The triglycerides averaged 150 mg/dL in each group, not remarkably high. [58] The ADA technical review by this author, published in Diabetes Care in January of 1998, showed an average triglyceride level of about 160 mg/dL in the United States for a similar population.[59] So the CARDS population's triglyceride levels were not far from that of the US population.

Figure 10. CARDS: lipid levels by treatment.
In CARDS, the average treatment difference in LDL cholesterol was 40% (Figure 10). There was also only a 1% change in HDL (unlike in other clinical trials, where atorvastatin 10 mg caused a 4% to 5% increase relative to placebo), and a 21% reduction in triglyceride levels (data not shown). This is a little better than what is usually seen with atorvastatin 10 mg at a triglyceride level of 150 mg/dL. In sum, CARDS results demonstrated a 40% LDL differential, no major change in HDL, and a 21% mg/dL triglyceride reduction between the atorvastatin 10-mg group and the placebo group.[58]

Figure 11. CARDS: cumulative hazard for primary endpoint
As this Kaplan-Meier graph shows, the atorvastatin arm had a 37% relative risk reduction (Figure 11). The primary endpoint of this study was reduction of fatal and nonfatal coronary events, strokes, and coronary revascularization procedures. By about a year into the study there was a fairly clear separation of LDL cholesterol levels, leading to the 37% reduction in cardiovascular events (significant at a .001 level). There were a total of 210 cardiovascular events; 127 in the placebo group and 83 in the atorvastatin group.[58] After 3.9 years of follow-up, the overall event rate was 2.2%. In the Steno-2 study discussed previously, there was a 5% event rate, [29] but those patients had type 2 diabetes with microalbuminuria, which can have a dramatic effect on cardiovascular events.[60] In CARDS, there was a 36% reduction in acute coronary events, including fatal and nonfatal MI, as well as a 31% reduction in revascularization procedures, and a 48% reduction in stroke in the atorvastatin group compared to the placebo group. And all of these were significant except for the coronary revascularization. [58] (Note that in US trials, we might expect to see as many coronary revascularizations as acute coronary events. The figure for coronary events is twice as high in the United Kingdom, most likely because they do many fewer bypasses.) As in the HPS, there was the same benefit in people whose baseline LDLs were below 120 mg/dL, half of whom were below 100 mg/dL.[58] This strongly reinforces the idea that patients with diabetes, even those without preexisting vascular disease, may benefit from statin therapy regardless of their LDL levels. It is important to note that statin therapy also had appreciable benefits for people who had lower HDL levels, and the effect seemed to be similar for people with both higher and lower triglyceride levels. This seems to show that, even in instances when fibric-acid treatment might be thought of as optimal, statins appear to work at least as well. In the CARDS data, there is an average 37% reduction in cardiovascular events as opposed to the 24% seen in VA-HIT. [56,58] One of the more impressive results from CARDS was the 27% reduction in all-cause mortality (data not shown). While the results from CARDS are not statistically significant, at P = .059 they were very close to significance. [58} To put this into perspective, the 4S study showed only a 30% reduction (P < .01). [45] However, the CARDS study did not include people with prevalent coronary heart disease with very high LDLs. To show an effect similar to what was seen in 4S for patients with diabetes but without CHD at baseline and who had LDLs averaging 120 mg/dL, as CARDS has done, is particularly impressive in favor of atorvastatin. Had the trial gone to completion, there would likely have been a significant difference in all-cause mortality.

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Summary of CARDS Findings
The CARDS data strongly demonstrate the safety and benefits of lipid-lowering drugs. People often talk about safety in terms of myopathy and liver function abnormalities, but what safety really consists of are hard events--whether you live or die. In this regard, the CARDS

data are impressive. The CARDS investigators saw a significant reduction in cardiovascular events in people who had type 2 diabetes but no preexisting vascular disease. They saw a reduction almost by half in stroke. The reductions achieved were independent of baseline LDLs. Interestingly, the investigators also found a slight decrease in noncardiovascular deaths, such as cancer and accidents (data not shown), factors that traditionally are a source of concern among statin users. Also, there were no cases of rhabdomyolysis, and LFTs were comparable in the 2 treatment groups. [58]

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Going Beyond Conventional LDL Goals
There is growing interest in the impact of lowering the LDL beyond conventional goals. The New England Journal of Medicine in April 2004 reported on the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial. This is a large study of 4162 patients who had the acute coronary syndrome (ACS) at study entry and were randomized to take pravastatin 40 mg or atorvastatin 80 mg, in a 2 by 2 factorial design with a 2-year mean follow-up. The primary endpoint of this trial is death from MI, unstable angina, revascularizations, or stroke, which is actually very similar to the primary endpoint in the CARDS trial. [61] This trial demonstrated a 49% reduction in LDL-C with atorvastatin 80 mg, and a 21% reduction with pravastatin 40 mg (data not shown). The LDLs achieved were 95 mg/dL in the pravastatin group (meeting NCEP criteria) and 62 mg/dL in the atorvastatin group (considerably better than NCEP). More importantly, the trial demonstrated a 16% reduction in clinical events that appeared to occur early after the initiation of high doses of atorvastatin. While this is not as large as was seen in CARDS, there was an active comparator (pravastatin 40 mg) in this trial. [61] In addition, this was a 2-year study, not a 4-year study, and so the implications of comparing primary prevention to ACS at baseline are not clear. Nevertheless, these results are impressive. Also worthy of note in the PROVE-IT trial is the subgroup analysis. In the placebo group, even among those subjects who had ACS, people with diabetes had a 60% higher event rate than people without diabetes. This demonstrates that, even among patients with documented coronary heart disease, diabetes further increases risk. The treatment effect was similar in the diabetic and nondiabetic groups although they were not quite statistically significant for the people with diabetes.[61] The LFT changes in PROVE-IT, as reflected by 3-fold LFT elevations, were significantly different among the treatment groups comprising PROVE-IT, although this is not really a surprise. As with CARDS, there were no cases of hepatitis and no cases of rhabdomyolysis, and the differences were not statistically significant for myalgias or creatine kinase elevations, so both therapies were well tolerated. [61]

Dyslipidemia: Etiology and Treatment Strategies
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Other Continuing Trials in Aggressive Lipid-Lowering Therapy

Table 6. Major Ongoing Lipid Trials
There are many other current trials that are attempting to examine the effect of more aggressive lipid lowering on outcomes (Table 6). PROVE-IT is an example of a study suggesting some high-risk subjects may benefit from LDLs much lower than 100 mg/dL. The NCEP has recently suggested that clinicians consider a lower LDL-C target (< 70 mg/dL) in very high-risk patients (NCEP White Paper). The 4 groups identified by the NCEP as high risk include people with cardiovascular disease with at least one of the following: diabetes, multiple risk factors (especially current cigarette smoking), metabolic syndrome, and ACS. [11] The new white paper also suggested that cardiovascular disease patients with an LDL cholesterol less than 100 mg/dL might benefit from lipid lowering. The recommendations suggested that LDL lowering be at least 30% to 40%.[62] More definitive data on this topic will come out of 2 big clinical trials, which are expected soon. These are Treatment to New Targets (TNT) (expected report at the 2005 meeting of the American College of Cardiology [ACC]) and the Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) (expected report at 2006 ACC). Each of these trials has about 10,000 subjects and both start with people with documented coronary heart disease. They also have similar primary endpoints of coronary artery disease death and nonfatal MI or stroke. TNT compares atorvastatin 10 mg to atorvastatin 80 mg; SEARCH compares simvastatin 20 mg to 80 mg, plus or minus vitamin B12 and folate. While SEARCH also sets out to test the homocysteine hypothesis, that topic is beyond the scope of this monograph. [63] In addition, there is the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which has about 6000 subjects, including a subgroup consisting of about 20% diabetes patients. Since this study is examining the use of fenofibrate, it may not change clinical practice because the data on statins are so persuasive. [63] Another study, called IDEAL (Increment Decrease in Endpoints through Aggressive Lipid Lowering), is being conducted in Scandinavia with 8888 subjects. IDEAL is examining the effect of simvastatin 20 mg to 40 mg vs atorvastatin 80 mg, on major cardiovascular endpoints.[64] Finally, there is the ongoing ACCORD trial mentioned earlier, one arm of which includes 5800 subjects and compares simvastatin 20 mg, plus or minus fenofibrate. This trial examines the effects of combination therapy, and has a narrow endpoint: Coronary artery disease death or nonfatal MI. The ACCORD trial is also studying 2 other very important new perspectives: First, 10,000 subjects will be treated to an A1C goal of less than 6%, vs the standard 7.5% target. As you can imagine, achieving an A1C of 6% is a very difficult task, but the investigators have actually gotten some of their subjects pretty close to that so far. Also, there is a systolic blood pressure intervention in a subgroup of 4200 subjects that compares a systolic blood pressure of less than 140 mm Hg to one of less than 120 mm Hg. [57] In conclusion, as the Steno 2 study shows, multiple interventions are likely to have dramatic effects on coronary heart disease. From 2002 to 2004, major new lipids trials (HPS, CARDS, and PROVE-IT) have shown that statins have dramatic effects in subjects with diabetes.[48,58,61] NCEP recommendations now suggest that all diabetic subjects, regardless of baseline LDL cholesterol, may benefit from statin therapy.[11] The LDL cholesterol goal is less than 100 mg/dL.[11,49] Additionally, it has suggested even more aggressive therapy may be indicated in diabetic subjects with cardiovascular disease, perhaps to as low as below 70 mg/dL.[62]

Joslin Diabetes Center Guidelines for Screening and Management of Dyslipidemia Associated with Diabetes
Editor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M. Haffner, MD Screening
Adults should be screened annually for lipid disorders with measurements of serum cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein (HDL-C), preferably fasting.

Lipid Goals
LDL-C: Less than 100 mg/dL Triglycerides: Less than 150 mg/dL (fasting) HDL-C: Greater than 40 mg/dL for men; greater than 50 mg/dL for women

Treatment
All patients should receive information about a meal plan designed to lower blood glucose (BG) and alter lipids, physical activity recommendations, and risk reduction strategies. (Consult with appropriate education discipline is preferred.) Institute therapy after abnormal values are confirmed.

If LDL-C greater than 100 mg/dL
Optimize glycemic control Refer to registered dietician (RD) for intensive dietary modification Consider referral to exercise specialist or diabetes educator (DE) for exercise prescription Recheck lipids within 6 weeks If LDL remains greater than 100, initiate medication with goal of lowering LDL by at least 30% or to less than 100, whichever is lower, preferably with a statin In patients with cardiovascular disease, the goal of LDL cholesterol should be lower (approximately 70 mg/dL), regardless of baseline level

If LDL-C less than 100 mg/dL
Consider statin therapy if age greater than 40 years, and 1 more cardiovascular disease (CVD) risk factor is present (hypertension, smoking, albuminuria, or family history of premature CVD).

Patients with LDL-C less than 100 mg/dL and triglycerides greater than or equal to 150 mg/dL or HDL-C less than 40 mg/dL
Optimize glycemic control Refer to RD for dietary modification Consider referral to exercise specialist for exercise prescription Recheck lipids within 6 weeks Consider medication if triglycerides greater than 200 and/or HDL less than 40 mg/dL (fibrate preferred if triglycerides greater than 500 mg/dL) In patients with triglyceride levels 200-499 mg/dL, calculate non-HDL-C (total minus HDL-C) and consider starting or titrating statin if non-HDL-C greater than 130

References

1. Alberti G, Zimmet P, Shaw J, Bloomgarden Z, Kaufman F, Silink M; Consensus Workshop Group. Type 2 diabetes in the young: the evolving epidemic: the International Diabetes Federation consensus workshop. Diabetes Care. 2004;27:1798-1811. 2. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;24:1047-1053. 3. Mokdad AH, Ford ES, Bowman BA, Nelson DE, et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care. 2000;23:1278-1283. 4. National Diabetes Data Group. Diabetes in America. 2nd ed. 1995. National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases. NIH Publication No. 95-1468. 5. Wilson PWF, Kannel WB. In: Ruderman N et al. eds. Hyperglycemia, Diabetes and Vascular Disease. Oxford;1992. 6. Krolewski AS, Warram JH, Valsania P, Martin BC, Laffel LM, Christlieb AR. Evolving natural history of coronary artery disease in diabetes mellitus. Am J Med. 1991;90(suppl 2A):56S-61S. 7. Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA. 1999;281:1291-1297. 8. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16:434-444. 9. Adler AI, Stratton IM, Neil HA, Yudkin JS, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412419. 10. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-234. 11. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497. 12. Reaven GM. Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med. 1993;44:121-131. Review. 13. Miyazaki Y, Glass L, Triplitt C, Wajcberg E, Mandarino LJ, DeFronzo RA. Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab. 2002;283:E1135E1143. 14. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2004;27:S5-S10. 15. Alberti KGM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. I. Diagnosis and classification of diabetes mellitus: provisional report of a WHO consultation. Diabet Med. 1998;15:539-553. 16. AACE Task Force on Insulin Resistance Syndrome. Available at: http://www.aace.com/clin/guidelines/ACEIRSPositionStatement.pdf 17. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287:356-359. 18. Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care. 2002;25:1177-1184. 19. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA. 1990;263:2893-2898. 20. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25:1129-1134. 21. Cowie CC et al. In: Diabetes in America. 2nd ed. Bethesda, Md; NIH Publication No. 95-1468;1995. 22. Ridker PM, Buring JE, Cook NR, Rifai N. C-Reactive protein, the metabolic syndrome, and risk of incident cardiovascular events. Circulation. 2003;107:391-397. 23. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A

24.

25. 26. 27.

28. 29. 30. 31. 32.

33. 34. 35. 36.

37. 38. 39. 40. 41. 42. 43.

44.

statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-511. Festa A, D'Agostino D, Howard G, Mykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000;102:42-47. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-1565. Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation. 2001;103:1933-1935. Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107:2409-2415. Nissen SE, Tuzco EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393. HOPE Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-153. Bohannon NJ. Coronary artery disease and diabetes. Postgrad Med. 1999;105:66-80. Stratton IM, Adler AI, Neil HA, Matthews DR, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405412. Libby P. In: Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders Co; 2001:995-1009; Libby P. J Intern Med. 2000;247:349-358. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witzum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915-924. Austin MA, Edwards KL. Small, dense low-density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol. 1996;7:167-171. Lamarche B, Tchernof A, Moorjani S, et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation. 1997;95:69-75. Doi H, Kugiyama K, Oka H, Sugiyama S, et al. Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redoxsensitive mechanism. Circulation. 2000;102:670-676. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683-689. Elliott WJ. Intensive antihypertensive treatment to the new lower blood pressure targets. Curr Hypertens Rep. 1999;1:313-319. Review. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713. Ballantyne CM. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol. 1998;82:3Q-12Q. Review. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA. 2004;291:335-342. Downs JR, Clearfield M, Weis S, Whitney E, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622. Goldberg RB, Mellies MJ, Sacks FM, Moyé LA, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup

45.

46.

47.

48.

49. 50.

51. 52. 53. 54. 55. 56.

57. 58.

59. 60. 61.

62.

63.

analyses in the Cholesterol And Recurrent Events (CARE) trial. Circulation. 1998;98:2513-2519. Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997;20:614-620. Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med. 1999;159:2661-2667. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005-2016. American Diabetes Association. Dyslipidemia management in adults with diabetes (Clinical Practice Recommendations 2004). Diabetes Care. 2004;27(Suppl 1):S68-S71. Snow V, Aronson MD, Hornbake ER, Mottur-Pilson C, Weiss KB; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2004;140:644-649. Jones PH, Davidson MH, Stein EA, Bays HE, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol. 2003;92:152-160. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001;21:1712-1719. Review. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation. 2000;101:207-213. Gagne C, Bays HE, Weiss SR, Mata P, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1084-1091. Haffner SM. Lipoprotein disorders associated with type 2 diabetes mellitus and insulin resistance. Am J Cardiol. 2002;90:55i-61i. Rubins HB, Robins SJ, Collins D, Fye CL, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-418. ACCORD Purpose. The ACCORD Trial Web Site. Available at: http://www.accordtrial.org/public/purpose.cfm. Accessed July 16, 2004. Colhoun HM, Betteridge JD, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled. Lancet. 2004;364:685-696. Haffner SM. Management of dyslipidemia in adults with diabetes. Diabetes Care. 1998;21:160-78. Review. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion: an independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19:1992-1997. Cannon CP, Braunwald E, McCabe CH, Rader DJ, et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Circulation. 2004;110:227-239. Evans M, Roberts A, Davies S, Rees A. Medical lipid-regulating therapy: current evidence, ongoing trials and future developments. Drugs. 2004;64:1181-1196. Review.

64. Pedersen TR, Faergeman O, Kastelein JJP, Olsson AG, et al. Design and baseline characteristics of the Incremental Decrease in End Points through Aggressive Lipid Lowering study. Am J Cardiol. 2004:94;720-804.

Authors and Disclosures
It is the policy of Joslin Diabetes Center to ensure fair balance, independence, objectivity, and scientific rigor in all programming. All faculty participating in CME activities sponsored by Joslin Diabetes Center are expected to present evidence-based data, identify and reference off-label product use, and disclose all relevant financial relationships existing within the past 12 months with those entities supporting the activity or any others whose products or services are discussed, including:

Any commercial product(s) or devices(s) The manufacturer(s) of any commercial products or devices The provider(s) of any commercial services If a faculty member has no information to disclose or refuses to do so, this information will also be provided.

Author
Richard S. Beaser, MD (Moderator) Assistant Clinical Professor of Medicine, Harvard Medical School; Medical Executive Director, Professional Education, Joslin Diabetes Center, Boston, MA Disclosure: Consultant: Amgen Inc., Amylin Pharmaceuticals, Inc., Wyeth Pharmaceuticals; Speakers Bureau: Aventis Pharmaceuticals, Wyeth Pharmaceuticals. Om P. Ganda, MD Associate Clinical Professor of Medicine, Harvard Medical School; Director, Joslin Diabetes Center Lipid Clinic, Boston, MA Disclosure: Grant/Research Support: KOS Pharmaceuticals, Inc.; Consultant: Merck & Co., Inc., Pfizer Inc, and Takeda Pharmaceuticals North America, Inc.; Speakers Bureau: GlaxoSmithKline, KOS Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc, Takeda Pharmaceuticals North America, Inc. Steven M. Haffner, MD Professor of Internal Medicine, Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center, San Antonio, Texas Disclosure: Consultant: GlaxoSmithKline, Merck & Co., Inc., and Pfizer Inc; Speaker's Bureau: GlaxoSmithKline, Merck & Co., Inc., and Pfizer Inc.

Registration for CME credit, the post test and the evaluation must be completed online. To access the activity Post Test and Evaluation link, please go to: http://www.medscape.com/viewprogram/3743_index