Dyslipidemia and Diabetes Reducing Macrovascular Risk

8/15/2019 Dyslipidemia and Diabetes Reducing Macrovascular Risk

1/27

These educational activities, certified by accredited providers, were not preparedby 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 significantfinancial relationships and mention of investigational drugs and unapprovedindications. Medscape has received a fee for posting these activities. Directquestions or comments to: [email protected].

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 originallyoffered 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 andother clinicians who manage people with diabetes.

Goal

This activity reviews the pathophysiology of type 2 diabetes andmacrovascular risk factors associated with the metabolic syndrome andidentifies appropriate markers to trigger intervention in patients with themetabolic syndrome in type 2 diabetes. It presents recent trial data andrecommendations for you to help your patients with diabetes achievethe new target treatment goals from the National Cholesterol EducationProgram.

Learning Objectives

Participants will be provided with evidence-based practical andclinically relevant information. At the completion of this activity, theparticipant should be able to:

1. Recognize people who are at risk for macrovascular disease basedon the presence of components of the metabolic syndrome2. Utilize an understanding of the interrelationships of the various

components of the metabolic syndrome to design and initiatecomprehensive preventive and treatment strategies aimed atreducing the risk of macrovascular disease

3. Identify patients with dyslipidemia early in its natural history dueto an improved understanding of the role hyperlipidemia can playin the development of macrovascular disease, particularly inpeople with type 2 diabetes

4. Design, implement, and manage effective treatments fordyslipidemias in people with diabetes and the metabolicsyndrome

Credits Available
http://www.medscape.com/http://www.medscape.com/http://users/kpumuk/convert/1/194423-195144.html#Authormailto:[email protected]://www.medscape.com/http://www.medscape.com/


2/27

Physicians - up to 1.25 AMA PRA Category 1 continuing physicianeducation credits

All other healthcare professionals completing continuing education credit for thisactivity will be issued a certificate of participation.

Participants should claim only the number of hours actually spent in completingthe educational activity.

Accreditation Statements

For Physicians

The Joslin Diabetes Center is accredited by the Accreditation Council forContinuing Medical Education to provide continuing medical education forphysicians.

The Joslin Diabetes Center designates this educational activity for a maximumof 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 theactivity.

For questions regarding the content of this activity, contact theaccredited provider for this CME/CE activity: [email protected] technical assistance, contact [email protected].

Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this onlineeducational activity. For information on applicability and acceptance ofcontinuing education credit for this activity, please consult yourprofessional 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 thetime actually spent in the activity. To successfully earn credit,participants must complete the activity online during the valid creditperiod that is noted on the title page.

Follow these steps to earn CME/CE credit:

1. Read the target audience, learning objectives, and authordisclosures.

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 thetop of the test. Medscape encourages you to complete the ActivityEvaluation 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 betallied in your CME/CE Tracker and archived for 5 years; at any pointwithin this time period you can print out the tally as well as thecertificates by accessing "Edit Your Profile" at the top of yourMedscape homepage.

The credit that you receive is based on your user profile.

This activity is supported by an unrestricted educational grant from Pfizer Inc.
mailto:[email protected]:[email protected]://px/linkto/circle-endo.3743?to=www.joslin.org/


3/27

Legal Disclaimer

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

Contents of This CME Activity

1. Diabetes, the Metabolic Syndrome, and Vascular Health: ClinicalInterrelationshipsEditor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.Haffner, MDA Growing EpidemicDiabetes and Cardiovascular RiskFactors that Contribute to Increased Risk of Cardiovascular Disease

Type 2 Diabetes as a Risk EquivalentDefining the Metabolic SyndromeOther Definitions of the Metabolic SyndromePrevalence and Impact of the Metabolic SyndromeDyslipidemia in DiabetesThe Vascular Injury in Patients With DiabetesThe Impact of Multifactorial InterventionCurrent Risk-Reduction Strategies

2. Dyslipidemia: Etiology and Treatment StrategiesEditor: Richard S. Beaser, MD; Faculty: Om P. Ganda, MD; Steven M.Haffner, MDCharacterizing Dyslipidemia in Type 2 Diabetes and the Metabolic SyndromeHow Blood Pressure and Glycemia Relate to Cardiovascular Disease andMicrovascular Complications

Current Control of Risk FactorsStatin Therapy in Patients With DiabetesCholesterol-Lowering Goals in Patients With DiabetesBenefits of Statin TherapyUse of Other Lipid-Lowering AgentsCombination Therapy for Lipid LoweringBackground on the CARDS TrialSummary of CARDS FindingsGoing Beyond Conventional LDL GoalsOther Continuing Trials in Aggressive Lipid-Lowering Therapy

3. Joslin Diabetes Center Guidelines for Screening and Management ofDyslipidemia Associated with DiabetesEditor: 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
http://viewarticle/496745_25http://viewarticle/496745_24http://viewarticle/496745_12http://viewarticle/496745_1


4/27

Table 1. Countries with Highest Number of Estimated Cases ofDiabetes (in millions) for 2000 and 2030

All evidence indicates that we are currently in the middle of a global diabetes epidemic. Infact, 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 isparticularly serious in countries like India and China, where resources to care for this growingnumber of people with diabetes are scarce.

Currently, the US has the third largest number of cases, with an estimated 18 million peoplewith diabetes. In addition, there are more than 50 million people with metabolic syndrome orinsulin 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 suchas 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 developsso does heart disease. While it is important to prevent diabetes, it has also become essentialto develop strategies for minimizing the risk of cardiovascular complications in people alreadydiagnosed with diabetes.


Interrelationships


Diabetes and Cardiovascular Risk

Macrovascular disease including coronary artery disease and other vascular events such asstroke 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 manyyears, 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 alreadyhave cardiovascular disease (CVD) by the time they are diagnosed with diabetes.

Epidemiologic studies such as the Framingham Heart Study reveal the impact of diabetes oncardiovascular events. A 30-year follow-up of subjects in that study found an increase in theprevalence of complications such as coronary heart disease, cardiac failure, intermittentclaudication, and stroke in patients with diabetes, compared with corresponding nondiabeticmen and women in the age range of 35 to 64 years. Women with diabetes showed arelatively greater increase in the risk of cardiovascular events than women without

diabetes.[5]


5/27

Figure 1. Cardiovascular mortality in type 2 diabetic patients vsnondiabetic cohort.

A study by Krolewski and colleagues compared the long-term follow-up status of the JoslinDiabetes Center patient population with the nondiabetic Framingham Heart Study population.This comparison revealed a 2-fold greater incidence of mortality from cardiovascular diseasein 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 ofcardiovascular disease in nondiabetic women is considerably lower than that in nondiabeticmen.

A comparison of the National Health and Nutrition Examination Survey (NHANES) data from1982 to 1984 vs that of 1971 to 1975 revealed that coronary artery disease mortality actuallydecreased by 36% and 27% in the nondiabetic men and women, respectively. However, thedecrease 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 coronaryheart disease mortality in people with diabetes? Secondly, what can be done to prevent themarked increases in cardiovascular events in both men and women with diabetes?

An analysis of the Multiple Risk Factor Intervention Trial (MRFIT), which enrolled more than350,000 men at its outset, including more than 5000 with diabetes, demonstrated that therisk in the diabetic population for death from cardiovascular disease was several-fold greaterfor 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 theneed for more intensive risk factor management in people with diabetes, because theirvasculature may be more susceptible to the effects of elevated cholesterol, high bloodpressure, smoking, and other risk factors.

Similarly, mean blood pressure of 144/82 mm Hg compared to 154/87 mm Hg in the UnitedKingdom Prospective Diabetes Study (UKPDS) resulted in major benefits in cardiovascular

endpoints.[9]


6/27

Figure 2. Incidence of myocardial infarction in people with type 2diabetes.

The incidence of myocardial infarction (MI) in people with diabetes was compared with thatof nondiabetics. After 7 years of follow-up, the people without diabetes had an MI rate ofabout 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 tothe notion that diabetes is a cardiovascular risk equivalent, which implies that people withdiabetes are considered at the same high risk for a cardiovascular event as people withoutdiabetes but a prior cardiovascular event.


Interrelationships


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 markedatherogenesis in patients with diabetes? (Table 2). Among the many factors involved, animportant 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


7/27

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 inmultiple, intermediary pathways, increased oxidative stress, endothelial dysfunction,hematological abnormalities leading to a procoagulant state, as well as hypertension andperhaps insulin resistance itself.


Interrelationships


Type 2 Diabetes as a Risk Equivalent

Evidence for increased risk of cardiovascular disease in people with diabetes led the AdultTreatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP) to labeltype 2 diabetes as a coronary heart disease (CHD) risk-equivalent in 2001. The 10-year riskof CHD in patients with diabetes is considered to be greater than 20%, which defines the

CHD risk-equivalence, according to ATP III.[11]


Interrelationships


Defining the Metabolic Syndrome

Metabolic syndrome is a diagnosis that has been in evolution. In 1988, Dr. Gerald Reavencoined the term "Syndrome X" to describe a cluster of abnormalities including glucose

intolerance, hyperinsulinemia, elevated triglycerides, low HDL, and hypertension.[12] Each ofthese markers is considered a risk factor for coronary artery disease. Since these factorsmay 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, iscentral obesity. Central obesity is an excessive deposition of fat in the abdominal area. It isassociated 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 havethe metabolic syndrome, which can precede type 2 diabetes. This may also result in coronaryartery 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


8/27

3).

These guidelines suggest examining 5 clinical parameters: Abdominal obesity (defined bywaist circumference), triglycerides greater than 150 mg/dL, low HDL cholesterol, bloodpressure 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 5factors defines the diagnosis of the metabolic syndrome.


Interrelationships


Other Definitions of the Metabolic Syndrome

The WHO has defined the metabolic syndrome slightly differently than the ATP III definitioncited 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: Abdominalobesity (defined by BMI rather than waist circumference), dyslipidemia, blood pressure of140/90 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 insulinresistance (such as high BMI, sedentary lifestyle, age above 40 years, membership in aminority 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-hourpost-glucose load level of greater than or equal to 140 mg/dL.

The similarities among these definitions are more important than the differences. The keypoint is that the metabolic syndrome increases macrovascular risk, and must be addressedclinically to reduce the incidence of vascular disease.

Diabetes, the Metabolic Syndrome, and Vascular Health: ClinicalInterrelationships


Prevalence and Impact of the Metabolic Syndrome

Twenty five percent of adults in the United States aged 20 to 79 years have the metabolicsyndrome 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 metabolicsyndrome. Type 2 diabetes is more common in all other ethnic populations when comparedto white populations, and the metabolic syndrome follows the same pattern. In fact, thehighest prevalence of the metabolic syndrome is in Mexican American men and MexicanAmerican 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 riskfactor for heart disease. An important longitudinal study of the large Mexican Americanpopulation of the city of San Antonio compared people over 8 years of age who remainednondiabetic to those who went on to develop diabetes. The individuals who eventuallydeveloped diabetes were those who had slightly more central abdominal fat, highertriglycerides, lower HDL cholesterol, and higher systolic blood pressure. They also statisticallyhad 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 sensitivitydecreased, HDL cholesterol decreased progressively, triglycerides increased, and both

systolic and diastolic blood pressure increased.[18,19]


9/27

Figure 3. Elevated risk of CVD prior to clinical diagnosis of type 2diabetes.

These data are supported by recent 20-year prospective analyses of the Nurses' HealthStudy. 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 arelative risk of developing heart disease of 1. For those who received a diagnosis of diabetesafter entry into the study, the relative risk for developing heart disease was 3.5 to 4. The riskfor those who had diabetes at baseline was 5. However, even those women who had not yetbeen diagnosed with diabetes were having cardiovascular events at a 2.8-fold higher ratethan those who remained nondiabetic throughout the study.

Diabetes, the Metabolic Syndrome, and Vascular Health: ClinicalInterrelationships


Dyslipidemia in Diabetes

Dyslipidemia in diabetes typically consists of lipid abnormalities that arise years before thediagnosis of diabetes. Whether a person has diabetes, metabolic syndrome, or insulinresistance, 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 hadtwice 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 moreelevated triglycerides than those who did not have diabetes.[21]

Furthermore, in MRFIT, when the age-adjusted cardiovascular disease death rate in patientswith type 2 diabetes was examined according to the levels of total cholesterol, there was aconsiderable increase, even among patients with mild elevations (eg, at less than 180 mg/dLof total cholesterol, equivalent to an LDL of 100 to 110 mg/dL). A similar examination of therelationship between elevated blood pressure and cardiovascular disease mortality showedthat not only was the risk obviously higher in people with high blood pressure, but peoplewith 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 thevasculature at each increment of blood pressure.


Interrelationships


10/27


The Vascular Injury in Patients With Diabetes

We still are attempting to understand the many factors that contribute to the accentuation ofatherogenesis in diabetes. Receiving a great deal of attention are the early events leading tothe formation of advanced glycosylation end products and the consequences of these endproducts, 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 toatherogenesis. In addition, current research shows that nitric oxide synthesis is reduced inthe presence of increased oxidative stress. It is also known that angiotensin II is involved inperpetuating this process.

Currently, there is considerable debate as to whether C-reactive protein (CRP) should bemeasured as a marker of subclinical endothelial inflammation. CRP is almost alwaysincreased in patients with type 2 diabetes, and may even precede the diagnosis. Data fromsuch trials as the Women's Health Study indicate that subclinical inflammation does correlatewith the increased risk of cardiovascular events. In that study, women with a normal CRP butdocumented metabolic syndrome or those with high CRP and no metabolic syndrome bothhad a decrease in risk-free survival relative to women who had neither the metabolicsyndrome 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 riskcategory 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 nondiabeticpopulation 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 riskdue 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 havereported 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.


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 multifactorialintervention in people with type 2 diabetes that examined the effects of a comprehensiveapproach to managing multiple risk factors in these patients. This study followed 160subjects with microalbuminuria over 8 years to examine the impact of 2 interventions. Allpatients received behavior modification, whereas only one group received, in addition, muchmore aggressive intervention for glycemic control, hypertension, dyslipidemia, and

microalbuminuria. [29]

The intensive therapy consisted of better diet, a practical exercise strategy, and smokingcessation. Glycemic control was attempted with oral agents and/or insulin as needed. Formanagement of hypertension, a number of agents, including diuretics, angiotensin convertingenzyme inhibitors (ACE-I), calcium channel blockers, and beta blockers were prescribed asneeded. Statins and fibrates were used as needed to achieve good control of both LDL and

triglyceride abnormalities.[29]


11/27

Figure 4. Steno-2: multifactorial intervention and CVD in type 2diabetes: impact on risk factors.

This long-term study demonstrates how difficult it is to achieve the desirable goals ofglycemic management. Even after comprehensive, intensive therapy and motivation, lessthan 20% of the subjects achieved normal hemoglobin HbA1c (A1C) concentrations less than

6.5% (Figure 4). About 70% of the patients in the intensive therapy group were able toachieve 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 asmany 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 2diabetes: impact on end points.

Although success was less than perfect in the reduction of risk factors, the risk factorimprovement was certainly better in the intensive therapy group. With this comprehensiveapproach, 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 autonomicneuropathy. This led the authors to conclude that a targeted, long-term, intensifiedintervention aimed at reducing multiple risk factors decreases quite significantly the risk of

both cardiovascular and macrovascular endpoints.[29]


12/27


Interrelationships


Current Risk-Reduction Strategies

The Steno-2 study and other evidence-based strategies support current treatmentrecommendations, 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 2diabetes 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 patientswith diabetes all over the world (including the United States) are not reaching recommendedgoals. Greater awareness of the need to reach those goals and further dissemination ofproven strategies should lead to better patient outcomes over the long run. It is important tonote 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 StrategiesEditor: 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 keyrole in disease progression.

Considerable data have accrued suggesting a key role for low-density lipoprotein (LDL) indetermining vascular risk, and it plays this role at multiple stages of the disease. During theinitiation phase, LDL contributes to the development of the atherogenic plaque. During the


13/27

progression phase, the Glagov hypothesis suggests that as the lipid core becomes muchlarger, 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 characterizesdyslipidemia in type 2 diabetes and the metabolic syndrome? The previous sectionunderscored that elevated triglycerides and average LDL cholesterol levels occur in mostpeople 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 areacted upon by lipoprotein lipase, they form remnants, are atherogenic, and have low high-

density lipoprotein (HDL). [37] These changes occur not only with type 2 diabetes, but also inpeople with the metabolic syndrome and prediabetes. Non-HDL cholesterol, which hasrecently 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 fordyslipidemia/hypertension: Botnia study.

The Botnia study, performed in Finland, looks at dyslipidemia (Figure 7), defined in this caseas high triglycerides and/or low HDL. This study reveals that the lipid abnormalities arerelatively more severe in people with type 2 diabetes when they are present, and atintermediate levels for people with impaired fasting glucose (IFG) and impaired glucosetolerance (IGT), relative to subjects with normal glucose tolerance. It also shows that not onlyare 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 samedegree of intensity in people with diabetes as in people with cardiovascular disease. This isbased on meeting 3 criteria:

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

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

3. The evidence is now overwhelming that lipid and blood pressure interventions toreduce coronary heart disease are equally effective in subjects with and withoutdiabetes.

Dyslipidemia: Etiology and Treatment Strategies


14/27


How Blood Pressure and Glycemia Relate to Cardiovascular Disease andMicrovascular Complications

Figure 8. MI and microvascular end points: incidence by mean systolicBP and A1C concentration.

Data from the United Kingdom Prospective Diabetes Study (UKPDS) show some similaritiesin 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 pressureover 10 years. The green line is myocardial infarction (MI), and the red line is microvasculardisease. Note that these 2 lines are parallel, meaning the effect of systolic blood pressure onmicrovascular 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 thatthere is no evidence that at very low blood pressures there might be an increased risk ofcomplications. In all studies in subjects with diabetes, both microvascular and macrovasculardisease declined with lower blood pressure.

This is an important issue because the Hypertension Optimal Treatment (HOT) trial, arandomized 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 andcovers a large range from 5.5% to 11%. It demonstrates that the risk of MI doubles from oneextreme to another, showing that A1C is related to CHD. However, if we calculate the size ofthe 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 fullyeliminate 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 risk30%, an effect similar to that seen in statin trials. [41] Therefore, it makes sense to use bothapproaches -- glucose and lipid control -- in at-risk people.

Another reason to further examine the chart on the right side of Figure 8 is to understandwhy the slope is relatively gentle, reflecting modest impact of A1C on event risk. A possibleexplanation is that there is already increased risk of cardiovascular disease prior to the onsetof type 2 diabetes. The increased triglycerides, decreased HDL, increased systolic bloodpressure, and increased glucose and insulin levels that these patients have are allcomponents seen in the various definitions of the metabolic syndrome, thus combining theireffects to increase macrovascular risk beyond that which relates to A1C alone.




15/27

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 whathas 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 ourpeople with diabetes under control. This is especially true since less than half of thesepeople have adequate cholesterol control, even though a LDL cholesterol level of 100 mg/dLcan be achieved by statins alone.



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 AirForce/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) and secondaryprevention trials such as Cholesterol and Recurrent Events (CARE), the ScandinavianSimvastatin Survival Study (4S), and Long-Term Intervention with Pravastatin in IschaemicDisease (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 aremore impressive than that for primary prevention. The Heart Protection Study (HPS) includedabout 6000 people with type 2 diabetes and examined the effects of simvastatin vs placeboon 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 thesame in people with diabetes who had either an LDL cholesterol below 116 mg/dL or above116 mg/dL. HPS was half secondary and half primary prevention, and the data by LDLcholesterol have not been broken out for the diabetic primary prevention population. Therewas also an analysis of people with type 1 diabetes in this study. About 600 people had type1 diabetes, and, although the results were not statistically significant, they showed the same

benefit as in the people with type 2 diabetes. [48]



Cholesterol-Lowering Goals in Patients With Diabetes


16/27

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 ofrecommendations, lowering LDL cholesterol is the primary goal, and the LDL goal is lessthan 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 ofPhysicians 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 WithDiabetes

Table 4 compares the ADA and the NCEP recommendations, showing how the primarytargets are the same. For the NCEP, non-HDL cholesterol (total cholesterol minus HDLcholesterol) 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


17/27

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, forpatients with poorly controlled diabetes, significant improvement in glycemic control cansometimes 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. Fenofibratewould 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 theADA 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 asthe first choice therapy, with bile acid sequestrants or nicotinic acid the second choice (thispredated the use of ezetimibe). The secondary goal is lowering non-HDL cholesterol; itbecomes 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 insulinresistance, but they have since modified those recommendations to suggest a fat intake ofbetween 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]



Benefits of Statin Therapy

Statin therapy inhibits cholesterol synthesis and increases LDL receptors. These agents arethe 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 isgenerally modest, but they differ in their effect. Meanwhile, the amount of triglyceridelowering also differs among statins and, importantly, it is much greater in people who startwith higher levels of triglycerides. In clinical trials, statins have been shown to offer up to a40% reduction in coronary heart disease and stroke. This effect appears to be attributablemainly to differences in LDL levels.

There has been considerable discussion of the pleiotropic effects of statins, although somethink 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 becollected 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 patientsMyopathy including rhabdomyolysis (very rare: Incidence = 0.5-1 in 10,000patients)Increased values on liver function tests (LFTs)

Contraindications to statin therapy include liver disease, defined by the US Food and DrugAdministration (FDA) as a repeated finding of 3-fold higher LFT levels than the upper limitsof normal. The potential for hepatotoxicity and the need to monitor LFTs is one of the majorlimitations 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 ofnormal. Creatine kinase should be measured at initiation of statin therapy to determine thepatient'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 about1 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, orfor those not using a combination of statins and fibric acids.

The risk of myopathy may increase with dose escalation. It also clearly occurs when statinsare used in combination with fibric acid, so in such instances it is important to weightreatment risks against anticipated benefits. Remember that when a statin is used incombination with a fibric acid, the fibric acid should be fenofibrate, and this combinedtreatment 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,


18/27

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



Use of Other Lipid-Lowering Agents

Ezetimibe is a newer agent that blocks cholesterol absorption. Studies show that, when usedas monotherapy, this agent lowers LDL by about 18%. It is mainly used in combination withstatins, and it has been suggested that it is equivalent to a 3-dose titration of statins (statin10 mg to 80 mg). Particularly with higher doses, the effect may be somewhat less, maybe a2-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 fewside effects; however, there currently are no long- term safety data on mono- or combinationtherapy with ezetimibe although a large-scale clinical trial in renal failure (n = 9000) iscurrently underway.

Fibric acids (including gemfibrozil and fenofibrate) are mainly indicated for treatment ofelevated 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% to10%. Adverse effects include gastrointestinal upset (8%), cholelithiasis, myositis, andabnormal LFTs. Gemfibrozil is not used as often, even though most of the available clinicaltrial data are actually with gemfibrozil. In the Veterans Affairs High-Density LipoproteinCholesterol 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 notnecessarily better than those of other studies, eg High-Risk Patients with Statins (HPS), orCollaborative Atorvastatin Diabetes Study (CARDS), discussed later in this document.

Nicotinic acid is probably the most controversial cholesterol-lowering drug. It is available bothin immediate release and extended release. The dose range has been truncated forextended 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 tohave many side effects, such as increases in LFT values, particularly the sustained releaseformulation. This is why it is contraindicated in patients with active liver disease orunexplained LFT elevations. Note that nicotinic acid worsens insulin resistance and increaseshyperglycemia. However, it can be used in patients with diabetes if they are relatively wellcontrolled and monitor their glucose carefully. In some patients, the benefit of this therapymay outweigh the risks.



Combination Therapy for Lipid Lowering

Combination therapy can dramatically improve the lipid profile, and its usage has thereforeincreased. This approach may result in a greater lowering of LDL than monotherapy(particularly when a statin is combined with nicotinic acid). Niacin can effectively lowerlipoprotein(a) (Lp(a)); however, it is important to remember that patients with diabetes do nothave particularly high LP(a) levels unless they have renal failure. In fact, patients with type 2diabetes may even have somewhat lower Lp(a) levels than nondiabetic subjects. Usingniacin in combination with a statin can significantly improve (increase) particle size, an effectnot usually seen with statin therapy alone. Niacin in conjunction with statins can alsodecrease fibrinogen levels. The benefit of treatment with fibric acid derivatives in combinationwith statins, as opposed to monotherapy, is also demonstrated by angiography studies andother data.

The downside of combination therapy includes cost and complexity. While many physiciansworry 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 ControlCardiovascular 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


19/27

and intensive blood pressure control on major cardiovascular-related events. This studyincludes 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 dataare unavailable at the time of the present writing. This study is discussed later in thisdocument.



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 studyexclusively performed in people with this condition. This was a primary preventionpopulation, with subjects having at study entry no history of previous MI or coronary heartdisease, 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 othercardiovascular 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 eventsoccurred or 4 years of double-blind treatment was completed, whichever came first. Thestudy 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 obesethan in a typical American population. (The average BMI among non-Asian US diabeticsubjects 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 LDLsabove 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 of1998, 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 ofthe US population.

Figure 10. CARDS: lipid levels by treatment.

In CARDS, the average treatment difference in LDL cholesterol was 40% (Figure 10). Therewas also only a 1% change in HDL (unlike in other clinical trials, where atorvastatin 10 mgcaused 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 atriglyceride 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]


20/27

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 coronaryevents, strokes, and coronary revascularization procedures. By about a year into the studythere was a fairly clear separation of LDL cholesterol levels, leading to the 37% reduction incardiovascular 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 wellas a 31% reduction in revascularization procedures, and a 48% reduction in stroke in theatorvastatin 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 asmany 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 patientswith diabetes, even those without preexisting vascular disease, may benefit from statintherapy regardless of their LDL levels.

It is important to note that statin therapy also had appreciable benefits for people who hadlower HDL levels, and the effect seemed to be similar for people with both higher and lowertriglyceride levels. This seems to show that, even in instances when fibric-acid treatmentmight 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-causemortality (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 includepeople with prevalent coronary heart disease with very high LDLs. To show an effect similarto what was seen in 4S for patients with diabetes but without CHD at baseline and who hadLDLs averaging 120 mg/dL, as CARDS has done, is particularly impressive in favor ofatorvastatin. Had the trial gone to completion, there would likely have been a significantdifference in all-cause mortality.



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


21/27

data are impressive.

The CARDS investigators saw a significant reduction in cardiovascular events in people whohad type 2 diabetes but no preexisting vascular disease. They saw a reduction almost byhalf in stroke. The reductions achieved were independent of baseline LDLs. Interestingly, theinvestigators also found a slight decrease in noncardiovascular deaths, such as cancer andaccidents (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 2treatment groups.[58]



Going Beyond Conventional LDL Goals

There is growing interest in the impact of lowering the LDL beyond conventional goals. TheNew England Journal of Medicine in April 2004 reported on the Pravastatin or AtorvastatinEvaluation and Infection Therapy (PROVE-IT) trial. This is a large study of 4162 patients whohad 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 meanfollow-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 inthe pravastatin group (meeting NCEP criteria) and 62 mg/dL in the atorvastatin group(considerably better than NCEP). More importantly, the trial demonstrated a 16% reductionin 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 eventrate than people without diabetes. This demonstrates that, even among patients with

documented coronary heart disease, diabetes further increases risk. The treatment effect wassimilar 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 significantlydifferent among the treatment groups comprising PROVE-IT, although this is not really asurprise. 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]



Other Continuing Trials in Aggressive Lipid-Lowering Therapy


22/27

Table 6. Major Ongoing Lipid Trials

There are many other current trials that are attempting to examine the effect of moreaggressive lipid lowering on outcomes (Table 6). PROVE-IT is an example of a studysuggesting some high-risk subjects may benefit from LDLs much lower than 100 mg/dL. TheNCEP has recently suggested that clinicians consider a lower LDL-C target (< 70 mg/dL) invery high-risk patients (NCEP White Paper). The 4 groups identified by the NCEP as highrisk 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 LDLcholesterol 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 expectedsoon. These are Treatment to New Targets (TNT) (expected report at the 2005 meeting ofthe 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 documentedcoronary heart disease. They also have similar primary endpoints of coronary artery diseasedeath 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 LipidLowering), is being conducted in Scandinavia with 8888 subjects. IDEAL is examining theeffect 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 includes5800 subjects and compares simvastatin 20 mg, plus or minus fenofibrate. This trialexamines the effects of combination therapy, and has a narrow endpoint: Coronary arterydisease death or nonfatal MI. The ACCORD trial is also studying 2 other very important newperspectives: First, 10,000 subjects will be treated to an A1C goal of less than 6%, vs thestandard 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 thatcompares 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 dramaticeffects 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 maybe indicated in diabetic subjects with cardiovascular disease, perhaps to as low as below 70

mg/dL.[62]


23/27

Joslin Diabetes Center Guidelines for Screening and Management

of Dyslipidemia Associated with Diabetes


Screening

Adults should be screened annually for lipid disorders with measurements of serumcholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) and high-densitylipoprotein (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 abnormalvalues 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 ofpremature CVD).

Patients with LDL-C less than 100 mg/dL and triglycerides greater than orequal 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


24/27

1. Alberti G, Zimmet P, Shaw J, Bloomgarden Z, Kaufman F, Silink M;Consensus Workshop Group. Type 2 diabetes in the young: the evolvingepidemic: the International Diabetes Federation consensus workshop. DiabetesCare. 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 theU.S.: 1990-1998. Diabetes Care. 2000;23:1278-1283.

4. National Diabetes Data Group.Diabetes in America. 2nd ed. 1995. NationalInstitutes of Health. National Institute of Diabetes and Digestive and KidneyDiseases. 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, ChristliebAR. 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 mortalityin 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 RiskFactor Intervention Trial. Diabetes Care. 1993;16:434-444.

9. Adler AI, Stratton IM, Neil HA, Yudkin JS, et al. Association of systolicblood pressure with macrovascular and microvascular complications of type 2diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412-419.

10. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality fromcoronary heart disease in subjects with type 2 diabetes and in nondiabeticsubjects with and without prior myocardial infarction. N Engl J Med .1998;339:229-234.

11. Executive Summary of the Third Report of the National CholesterolEducation Program (NCEP) Expert Panel on Detection, Evaluation, andTreatment 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): anexpanded 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 intype 2 diabetes mellitus. Am J Physiol Endocrinol Metab. 2002;283:E1135-E1143.

14. American Diabetes Association. Diagnosis and Classification of DiabetesMellitus. Diabetes Care. 2004;27:S5-S10.

15. Alberti KGM, Zimmet PZ. Definition, diagnosis and classification of diabetesmellitus and its complications. I. Diagnosis and classification of diabetesmellitus: 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 amongUS adults: findings from the third National Health and Nutrition ExaminationSurvey. JAMA. 2002;287:356-359.

18. Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis modelassessment of insulin resistance in relation to the incidence of cardiovasculardisease: 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 theclock for coronary heart disease start ticking before the onset of clinicaldiabetes? 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 2diabetes. Diabetes Care. 2002;25:1129-1134.

21. Cowie CC et al. In:Diabetes in America. 2nd ed. Bethesda, Md; NIHPublication No. 95-1468;1995.

22. Ridker PM, Buring JE, Cook NR, Rifai N. C-Reactive protein, the metabolicsyndrome, 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
http://www.aace.com/clin/guidelines/ACEIRSPositionStatement.pdf


25/27

statement for healthcare professionals from the Centers for Disease Controland Prevention and the American Heart Association. Circulation.2003;107:499-511.

24. 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.

25. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactiveprotein and low-density lipoprotein cholesterol levels in the prediction of firstcardiovascular events. N Engl J Med. 2002;347:1557-1565.

26. Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect ofhydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on highsensitive C-reactive protein levels. Circulation. 2001;103:1933-1935.

27. Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibecoadministered with atorvastatin in 628 patients with primaryhypercholesterolemia: a prospective, randomized, double-blind trial.Circulation. 2003;107:2409-2415.

28. Nissen SE, Tuzco EM, Schoenhagen P, et al. Effect of intensive comparedwith moderate lipid-lowering therapy on progression of coronaryatherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080.

29. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O.

Multifactorial intervention and cardiovascular disease in patients with type 2diabetes. N Engl J Med. 2003;348:383-393.

30. HOPE Investigators. Effects of an angiotensin-converting enzyme inhibitor,ramipril, on cardiovascular events in high-risk patients. N Engl J Med .

2000;342:145-153.31. Bohannon NJ. Coronary artery disease and diabetes. Postgrad Med.

1999;105:66-80.32. Stratton IM, Adler AI, Neil HA, Matthews DR, et al. Association of

glycaemia with macrovascular and microvascular complications of type 2diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412.

33. 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.

34. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witzum JL. Beyondcholesterol: modifications of low-density lipoprotein that increase itsatherogenicity. N Engl J Med. 1989;320:915-924.

35. Austin MA, Edwards KL. Small, dense low-density lipoproteins, the insulinresistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol.1996;7:167-171.

36. Lamarche B, Tchernof A, Moorjani S, et al. Small, dense low-densitylipoprotein particles as a predictor of the risk of ischemic heart disease inmen: prospective results from the Quebec Cardiovascular Study. Circulation.1997;95:69-75.

37. Doi H, Kugiyama K, Oka H, Sugiyama S, et al. Remnant lipoproteins induceproatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation. 2000;102:670-676.

38. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR,Groop L. Cardiovascular morbidity and mortality associated with themetabolic syndrome. Diabetes Care. 2001;24:683-689.

39. Elliott WJ. Intensive antihypertensive treatment to the new lower blood

pressure targets. Curr Hypertens Rep. 1999;1:313-319. Review.40. Tight blood pressure control and risk of macrovascular and microvascular

complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes StudyGroup. BMJ. 1998;317:703-713.

41. Ballantyne CM. Low-density lipoproteins and risk for coronary artery disease.Am J Cardiol. 1998;82:3Q-12Q. Review.

42. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vasculardisease among adults with previously diagnosed diabetes. JAMA.2004;291:335-342.

43. Downs JR, Clearfield M, Weis S, Whitney E, et al. Primary prevention ofacute coronary events with lovastatin in men and women with averagecholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas CoronaryAtherosclerosis Prevention Study. JAMA. 1998;279:1615-1622.

44. Goldberg RB, Mellies MJ, Sacks FM, Moy LA, et al. Cardiovascular eventsand their reduction with pravastatin in diabetic and glucose-intolerant

myocardial infarction survivors with average cholesterol levels: subgroup


26/27

analyses in the Cholesterol And Recurrent Events (CARE) trial. Circulation.1998;98:2513-2519.

45. Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, ThorgeirssonG. Cholesterol lowering with simvastatin improves prognosis of diabeticpatients with coronary heart disease. A subgroup analysis of the ScandinavianSimvastatin Survival Study (4S). Diabetes Care. 1997;20:614-620.

46. Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, PedersenTR, Kjekshus J, Pyorala K. Reduced coronary events in simvastatin-treatedpatients with coronary heart disease and diabetes or impaired fasting glucoselevels: subgroup analyses in the Scandinavian Simvastatin Survival Study.Arch Intern Med. 1999;159:2661-2667.

47. Prevention of cardiovascular events and death with pravastatin in patientswith coronary heart disease and a broad range of initial cholesterol levels. TheLong-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) StudyGroup. N Engl J Med. 1998;339:1349-1357.

48. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection StudyCollaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomisedplacebo-controlled trial. Lancet. 2003;361:2005-2016.

49. American Diabetes Association. Dyslipidemia management in adults withdiabetes (Clinical Practice Recommendations 2004). Diabetes Care .

2004;27(Suppl 1):S68-S71.50. 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 clinicalpractice guideline from the American College of Physicians. Ann Intern Med.2004;140:644-649.

51. Jones PH, Davidson MH, Stein EA, Bays HE, et al. Comparison of theefficacy and safety of rosuvastatin versus atorvastatin, simvastatin, andpravastatin across doses (STELLAR Trial). Am J Cardiol. 2003;92:152-160.

52. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutarylcoenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol.2001;21:1712-1719. Review.

53. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation.2000;101:207-213.

54. Gagne C, Bays HE, Weiss SR, Mata P, et al. Efficacy and safety of ezetimibeadded to ongoing statin therapy for treatment of patients with primaryhypercholesterolemia. Am J Cardiol. 2002;90:1084-1091.

55. Haffner SM. Lipoprotein disorders associated with type 2 diabetes mellitusand insulin resistance. Am J Cardiol. 2002;90:55i-61i.

56. Rubins HB, Robins SJ, Collins D, Fye CL, et al. Gemfibrozil for thesecondary prevention of coronary heart disease in men with low levels ofhigh-density lipoprotein cholesterol. Veterans Affairs High-DensityLipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med.1999;341:410-418.

57. ACCORD Purpose. The ACCORD Trial Web Site. Available at:http://www.accordtrial.org/public/purpose.cfm. Accessed July 16, 2004.

58. Colhoun HM, Betteridge JD, Durrington PN, et al. Primary prevention ofcardiovascular disease with atorvastatin in type 2 diabetes in the CollaborativeAtorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled. Lancet. 2004;364:685-696.

59. Haffner SM. Management of dyslipidemia in adults with diabetes. Diabetes

Care. 1998;21:160-78. Review.60. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS.

Urinary albumin excretion: an independent predictor of ischemic heartdisease. Arterioscler Thromb Vasc Biol. 1999;19:1992-1997.

61. Cannon CP, Braunwald E, McCabe CH, Rader DJ, et al. Pravastatin orAtorvastatin Evaluation and Infection Therapy-Thrombolysis in MyocardialInfarction 22 Investigators. Intensive versus moderate lipid lowering withstatins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.

62. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, et al. Implications ofrecent clinical trials for the National Cholesterol Education Program AdultTreatment Panel III guidelines. National Heart, Lung, and Blood Institute;American College of Cardiology Foundation; American Heart Association.Circulation. 2004;110:227-239.

63. 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.


27/27

64. Pedersen TR, Faergeman O, Kastelein JJP, Olsson AG, et al. Design andbaseline characteristics of the Incremental Decrease in End Points throughAggressive 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 byJoslin Diabetes Center are expected to present evidence-based data, identify and referenceoff-label product use, and disclose all relevant financial relationships existing within the past12 months with those entities supporting the activity or any others whose products orservices are discussed, including:

Any commercial product(s) or devices(s)The manufacturer(s) of any commercial products or devicesThe 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 MedicalSchool; Medical Executive Director, Professional Education,Joslin Diabetes Center, Boston, MA

Disclosure: Consultant: Amgen Inc., Amylin Pharmaceuticals,Inc., Wyeth Pharmaceuticals; Speakers Bureau: AventisPharmaceuticals, Wyeth Pharmaceuticals.

Om P. Ganda, MD

Associate Clinical Professor of Medicine, Harvard MedicalSchool; Director, Joslin Diabetes Center Lipid Clinic, Boston,MA

Disclosure: Grant/Research Support: KOS Pharmaceuticals,Inc.; Consultant: Merck & Co., Inc., Pfizer Inc, and TakedaPharmaceuticals 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 HealthScience 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 becompleted online.To access the activity Post Test and Evaluation link, please go to:http://www.medscape.com/viewprogram/3743_index
http://viewprogram/3743_index

Dyslipidemia and Diabetes Reducing Macrovascular Risk

Documents