Lipid management in diabetic patients: lessons from prevention trials

Lipid Management in Diabetic Patients: Lessons from Prevention Trials Antonio M. Gotto, Jr., MD, DPhil

Diabetes is associated with greatly enhanced risk for coronary heart disease (CHD), a correlation that justifies aggressive risk intervention in diabetic individuals. Lipid abnormalities in diabetes frequently consist of elevated triglyceride and low-density lipoprotein cholesterol levels and low high-density lipoprotein cholesterol levels. Subgroup analyses of primary and secondary prevention trials with fibrates and statins indicate that lipid modification in diabetic patients is associated with significant CHD risk reduction. In 1 angiographic study (Diabetes Atherosclerosis Intervention Study) fibrate treatment was shown to reduce the rate of atherosclerotic progression. A primary prevention study of statin treatment (West of Scotland Coronary Prevention Study) showed reduced risk for progression to diabetes in a post hoc analysis. Optimal lipid-modifying treatment in individuals with diabetes remains to be defined. Upcoming trials with diabetic cohorts will improve our understanding of how lipid treatment affects CHD risk in this patient population. Am J Med. 2002; 112(8A):19S–26S. © 2002 by Excerpta Medica, Inc.

From Weill Medical College of Cornell University, New York, New York, USA. Address correspondence to Antonio M. Gotto, Jr., MD, DPhil, c/o Paula Trushin, Weill Medical College of Cornell University, 445 East 69th Street, Olin Hall 205, New York, New York 10021. © 2002 by Excerpta Medica, Inc. All rights reserved.

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oth type 1 and type 2 diabetes mellitus are independent risk factors for atherosclerosis. Coronary heart disease (CHD) occurs more frequently and at a younger age in diabetic individuals than in the general population and is the cause of death in more than half of the adult diabetic population.1 A recent study of patients in eastern and western Finland (known as the East-West study) showed that the 7-year rate of myocardial infarction (MI) in individuals with type 2 diabetes and no prior MI (20.2%) is greater than that in nondiabetic individuals with prior MI (18.8%), suggesting that diabetes is associated with a CHD event risk comparable to that seen among nondiabetic patients with established CHD.2 Diabetic patients, particularly those with type 2 diabetes, often present with elevated triglyceride (TG) and lowdensity lipoprotein (LDL) cholesterol levels and reduced high-density lipoprotein (HDL) cholesterol levels. This can be seen in a study that applied 1997 American Diabetes Association (ADA) criteria to an adult sample from the National Health and Nutrition Examination Survey III (NHANES III) database. Figure 1 presents the rates for lipid values by glucose status. Rate ratios were then calculated comparing lower and higher lipid groups. The rate ratios indicate that the prevalence of lipid risk factors increased among those with impaired fasting glucose (IFG) and diabetes mellitus (DM).3 This study also indicated that the incidence of CHD increased with worsening glucose status but that CHD prevalence was more strongly associated with the presence of traditional CHD risk factors (age, family history, blood pressure, HDL cholesterol, smoking, and lack of recent exercise) than with hyperglycemia. This review will emphasize management of cardiovascular risk in diabetic patients based on management of the most common lipid disorders seen in diabetic dyslipidemia, including elevated TG levels and low HDL cholesterol. However, lipid control alone does not eliminate all macrovascular risk in diabetic patients. Continued study of the diabetic state itself, such as elucidating the roles of free fatty acids, free radicals, inflammatory markers, or endothelial dysfunction, may yield key insights for future preventive strategies in this highrisk group.

LIPID GOALS Analyses of outcomes in low HDL cholesterol subgroups in the 5 major primary or secondary prevention trials involving statin therapy have shown that substantial re0002-9343/02/$20.00 19S PII S0002-9343(02)01086-0

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Figure 1. Application of 1997 American Diabetes Association diagnostic criteria to an adult sample from the National Health and Nutrition Examination Survey (NHANES) III database representing 170.5 million individuals with normal fasting glucose (NFG), impaired fasting glucose (IFG), and diabetes mellitus (DM). Within each lipid category, prevalence rates for NFG, IFG, and DM are presented. The numbers in parentheses represent the estimated millions (M) of people in the United States (1988 to 1994), based on the sampling weights. DM (FG) ⫽ DM based on fasting plasma glucose; DM (Hx) ⫽ self-reported (history of) DM. HDL-C ⫽ high-density lipoprotein cholesterol levels; LDL-C ⫽ low-density lipoprotein cholesterol levels; TG ⫽ triglyceride levels. (Adapted from Am J Cardiol.3)

ductions in CHD events occurred with modest HDL cholesterol increases (Figure 2).4 –9 Because the primary lipid-modifying effect of statins is to reduce LDL cholesterol levels, the results of these studies reinforce the importance of LDL cholesterol lowering as the main target of therapy, even in low HDL cholesterol subgroups. The role of increasing HDL cholesterol levels in reducing CHD risk remains to be elucidated. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), in which 25% of patients had diabetes, enrolled men whose primary lipid abnormality was low HDL cholesterol (mean of 32 mg/ dL). In this study, gemfibrozil treatment was associated with a 22% reduction in primary CHD end points compared with placebo, with no change in LDL cholesterol, a 31% reduction in TG, and a 6% increase in HDL choles20S

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terol. The investigators concluded that much of the preventive benefit was associated with the HDL cholesterol increase.9 Similar benefits have been reported in other clinical end point trials in populations with low HDL cholesterol.10 In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS; mean initial HDL cholesterol levels of 36 mg/dL in men and 40 mg/dL in women), lovastatin treatment was associated with a 37% reduction in CHD events in the context of a 25% decrease in LDL cholesterol, a 15% decrease in TG levels, and a 6% increase in HDL cholesterol.4 In the secondary prevention Bezafibrate Infarction Prevention (BIP) study, which enrolled 3,090 patients, those taking bezafibrate had a nonsignificant 7.3% decrease in the cumulative probability of a primary end point event. According to a post hoc subgroup analysis, however, the

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Figure 2. Reductions in primary coronary heart disease (CHD) end point event rates compared with placebo in low high-density lipoprotein (HDL) cholesterol subgroups in major primary and secondary prevention trials with statins and in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT). Baseline HDL cholesterol levels (numbers in parentheses) and percent reduction in end point events are for low HDL cholesterol subgroups. Also shown are percent increases in HDL cholesterol for the overall study samples. Because these studies differ in their definitions of “primary end point,” this figure is not designed to compare the studies with each other. *In 4S, the primary end point was total mortality; CHD events were secondary end points. AFCAPS/TexCAPS ⫽ Air Force/Texas Coronary Atherosclerosis Prevention Study; CARE ⫽ Cholesterol and Recurrent Events trial; LIPID ⫽ Long-Term Intervention with Pravastatin in Ischaemic Disease study; 4S ⫽ Scandinavian Simvastatin Survival Study; WOSCOPS ⫽ West of Scotland Coronary Prevention Study. (Data from JAMA,4 Lancet,6 and N Engl J Med.5,7,9)

reduction in the cumulative probability was 39.5% in patients with TG levels ⱖ200 mg/dL (P ⫽ 0.02). This indicates the importance of considering a patient’s total lipid profile when determining the appropriate lipid-lowering therapy.11 The West of Scotland Coronary Prevention Study (WOSCOPS), the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, and VAHIT found that reductions in CHD risk were similar for patients with elevated or with lower baseline TG concentrations. However, the Cholesterol and Recurrent Events (CARE) trial reported that the reduction in CHD risk was markedly less in patients with high baseline TG levels compared with those who had lower TG levels.7 These observations raise the issue of what might constitute appropriate lipid-modifying therapy in diabetic patients with the characteristic lipid profile of elevated TG and LDL cholesterol levels and reduced HDL cholesterol—that is, whether a statin or a fibrate is more appropriate in patients who may qualify for treatment with either one of these classes of agents. Thus far, no trials have been completed that have prospectively evaluated the effects of lipid-modifying treatment on macrovascular events in an exclusively diabetic patient population.

However, as reviewed below, findings in diabetic subpopulations in major prevention trials suggest clinical benefits with both types of treatment.

EVIDENCE OF CLINICAL BENEFIT OF LIPID MODIFICATION In the secondary prevention VA-HIT study (N ⫽ 2,531), which enrolled men with and without diabetes, gemfibrozil treatment was associated with a 22% reduction in the risk for CHD death or nonfatal MI compared with placebo.9 Similarly, there was a 24% reduction in the relative risk for CHD death, nonfatal MI, or stroke. Among the patients with diabetes, 28% receiving gemfibrozil experienced a CHD event (CHD death, nonfatal MI, or stroke) compared with 36% receiving placebo (P ⫽ 0.05). For the nondiabetic patients, the event rates were 18% with gemfibrozil versus 23% with placebo (P ⫽ 0.009). In the primary-prevention Helsinki Heart Study (HHS), there were 135 patients with type 2 diabetes. Among these patients, 2 on gemfibrozil and 8 taking placebo had a CHD event (P ⫽ 0.19).12 Evidence of the benefit of fibrate treatment also comes from the Diabetes Atherosclerosis Intervention Study (DAIS), the first re-

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ported angiographic study to examine the effects of correcting lipoprotein abnormalities in a cohort consisting only of patients with type 2 diabetes. A total of 418 patients (305 men and 113 women) with mean baseline total cholesterol of 215 mg/dL, LDL cholesterol of 133 mg/ dL, HDL cholesterol of 40 mg/dL, and TG levels of 214 mg/dL and at least 1 coronary atherosclerotic lesion visible on angiography, received micronized fenofibrate or placebo for at least 3 years.13 Patients receiving fenofibrate experienced a 40% reduction in the rate of progression of localized atherosclerotic disease, with a 10% decrease in total cholesterol, a 6% decrease in LDL cholesterol, a 29% decrease in TG, and a 6% increase in HDL cholesterol. Although the study was not designed to assess clinical outcomes, fenofibrate treatment was associated with a nonsignificant 23% reduction in coronary events. With regard to statin therapy and CHD events, lovastatin treatment in the primary prevention AFCAPS/TexCAPS trial was associated with a nonsignificant 33% reduction in CHD risk in 155 patients with type 2 diabetes (compared with a 37% risk reduction in the overall population).4 In the secondary-prevention CARE trial, there was a 25% risk reduction (P ⫽ 0.05) with pravastatin among 586 diabetic patients (24% risk reduction in the overall study sample).7 In the Scandinavian Simvastatin Survival Study (4S), simvastatin treatment was associated with a 55% reduction in the risk for a major CHD event (P ⫽ 0.002) among 202 diabetic patients (34% risk reduction in the overall study sample)6,14; a more recent 4S analysis using 1997 ADA criteria for the diagnosis of diabetes found a 42% risk reduction (P ⫽ 0.001) with statin treatment among 483 diabetic patients.15 In the LIPID trial, pravastatin treatment led to a nonsignificant 19% reduction in CHD risk among 782 patients with diabetes (25% risk reduction in the overall population).5 Analysis of outcomes with pravastatin treatment in the Pravastatin Pooling Project, which included patients from CARE, LIPID, and WOSCOPS, showed that pravastatin treatment was associated with a 26% reduction (P ⫽ 0.002) in CHD death, nonfatal MI, percutaneous coronary intervention, or coronary artery bypass graft surgery among a total of 1,444 diabetic patients (23% risk reduction, P ⬍0.001, among 18,324 nondiabetic patients).16 In addition to lowering cardiovascular risk in diabetic subgroups, statin treatment in the primary prevention WOSCOPS was linked to a significant 30% reduction in the risk for developing diabetes on both univariate and multivariate analysis (Figure 3).17 Although the explanation for the possible protective benefit of pravastatin in diabetes is unclear, recent evidence suggests that it may involve the ability of the drug to lower TG levels, decrease inflammation, and restore endothelial function. Pravastatin has been shown to reduce circulating levels of the proinflammatory cytokines interleukin 6 and tumor necrosis factor-␣,18 which have been implicated in the met22S

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abolic syndrome, a constellation of lipid and nonlipid abnormalities associated with insulin resistance.19 Consequently, the anti-inflammatory effect of pravastatin may interrupt the sequence of events that leads to insulin resistance.17 The nonlipid (ie, “pleiotropic”) benefits of statins have not been fully elucidated. However, the fact that proinflammatory factors, insulin resistance, and elevated TG levels are all features of the metabolic syndrome20 suggests a possible pathophysiologic connection and underscores the importance of early recognition and treatment of lipid abnormalities in individuals who appear to be at risk for developing insulin resistance.

TREATMENT OF LIPID ABNORMALITIES IN INDIVIDUALS WITH DIABETES Should patients with low HDL cholesterol, including those with diabetes, receive statin treatment, or should they receive fibrate treatment? Lessons from the fibrate trials include the findings that low HDL cholesterol is an important synergistic risk factor for CHD and that HDL cholesterol and TG modification can reduce the risk for recurrent CHD. On the other hand, the statin trials have shown that statin treatment appears to attenuate the risk associated with low HDL cholesterol, that targeting LDL cholesterol in primary prevention patients with belowaverage HDL cholesterol yields clinical benefit, and that HDL cholesterol (and its constituents) may be important predictors of risk in low- to moderate-risk patients. It may be that the best approach is to use statin therapy in patients whose primary lipid abnormality is elevated LDL cholesterol, to begin with fibrate therapy in those with severe TG elevations, and to use combination therapy in patients with mixed dyslipidemia. Table 1 shows the ADA risk stratification based on lipid levels for individuals with type 2 diabetes.21 Women in general have higher HDL cholesterol levels than men; the ADA therefore recommends that these HDL cholesterol criteria be increased by 10 mg/dL for women. Guidelines for treatment based on LDL cholesterol level are shown in Table 2. Drug treatment should be initiated after lifestyle interventions are tried, except in those with established CHD or LDL cholesterol levels ⱖ200 mg/dL. In these patients, drug therapy and behavioral intervention should be initiated simultaneously. Because of the increased risk for CHD associated with diabetes, the ADA recommends an LDL cholesterol goal of ⬍100 mg/dL in diabetic individuals without CHD, the same level that the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines recommend for all patients with preexisting CHD or CHD risk equivalents.20 The new ATP III guidelines identify diabetes as a CHD risk equivalent (it was a major risk factor in the 1993 NCEP ATP II guidelines)22 and recommend the same aggressive treatment in diabetic individuals as in patients

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Figure 3. (Top) Risk for developing diabetes for pravastatin (n ⫽ 57) or placebo (n ⫽ 82) recipients participating in the West of Scotland Coronary Prevention Study (multivariate analysis). (Bottom) Multivariate analysis of risk factors for developing diabetes. Shown are multivariate hazard ratios with 95% confidence intervals. HDL ⫽ high-density lipoprotein; WCC ⫽ white cell count. (Adapted with permission from Circulation.17)

with established CHD.20 This means that a diabetic patient with an LDL cholesterol level ⱖ130 mg/dL will likely require pharmacologic treatment to reach a goal of ⬍100 mg/dL. For individuals with an LDL cholesterol concentration of 100 to 129 mg/dL, drug therapy is optional, but therapeutic lifestyle changes (TLC) involving both diet and physical activity are essential. Because poor diet can undermine the effects of lipid-lowering therapy, all patients must continue TLC even after they have begun drug treatment. For individuals with the high TG concentrations characteristic of diabetes, it is particularly impor-

tant to monitor carbohydrate intake (50% to 60% of total calories) and fat intake (25% to 35% of total calories with specific limits for saturated, monounsaturated, and polyunsaturated fat). Carbohydrates, especially those derived from commercially baked goods and other processed foods, can raise TG and lower HDL levels. Therefore, complex carbohydrates from whole grains, fruits, and vegetables are preferable. The primary goal of CHD risk reduction is to lower LDL cholesterol levels. In addition, the ATP III guidelines classify the metabolic syndrome as a secondary therapeu-

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Table 1. American Diabetes Association Risk Stratification Based on Lipid Levels in Adults with Type 2 Diabetes*† Risk Stratification (mg/dL) Risk

LDL Cholesterol

HDL Cholesterol‡

Triglycerides

ⱖ130 100–129 ⬍100

⬍35 35–45 ⬎45

ⱖ400 200–399 ⬍200

High Borderline Low

HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein. * Type 1 diabetes patients with good glycemic control tend to have lipoprotein levels that are normal or better than normal. Although their lipoprotein composition may be abnormal, the effect of such abnormalities on coronary heart disease (CHD) risk is unknown. † Medical nutrition therapy should be attempted before pharmacologic therapy is initiated in patients without preexisting CHD and LDL cholesterol levels of 100 mg/dL to 129 mg/dL. Because a large proportion of patients with diabetes die en route to the hospital after experiencing a coronary event, “secondary prevention” is moot. Therefore, patients with clinical cardiovascular disease or LDL cholesterol levels ⱖ200 mg/dL should start drug treatment and behavioral modification (e.g., medical nutrition therapy) concurrently.21 ‡ Because HDL cholesterol levels tend to be higher in women (at least in nondiabetic women) than in men, the American Diabetes Association recommends adding 10 mg/dL to HDL cholesterol levels shown for risk stratification in women.21 Reprinted with permission from Diabetes Care.21

Table 2. American Diabetes Association Treatment Thresholds Based on Low-Density Lipoprotein (LDL) Cholesterol Levels in Adults with Type 2*† Diabetes: Treatment Initiation and LDL Cholesterol Goals Medical Nutrition Therapy

Drug Therapy

Initiation Level (mg/dL)

Goal (mg/dL)

Initiation Level (mg/dL)

Goal (mg/dL)

With CHD, PVD, or CVD

ⱖ100

⬍100

ⱖ100

⬍100

Without CHD, PVD, or CVD

ⱖ100

⬍100

ⱖ130

⬍100

‡

CHD ⫽ coronary heart disease; CVD ⫽ cerebrovascular disease; PVD ⫽ peripheral vascular disease. See Table 1 for other abbreviations. * See footnote in Table 1. † See footnote in Table 1. ‡ For patients with LDL cholesterol between 100 mg/dL and 129 mg/dL, a variety of treatment strategies is available, including more aggressive medical nutrition therapy and pharmacologic treatment with a statin. In addition, if the HDL cholesterol is ⬍40 mg/dL, a fibrate may be used. Reprinted with permission from Diabetes Care.21

tic target. Clinically characterized by abdominal obesity, impaired fasting glucose (fasting glucose ⱖ110 mg/dL), high TG levels (ⱖ150 mg/dL), low HDL cholesterol levels (⬍40 mg/dL in men, ⬍50 mg/dL in women), and elevated blood pressure (ⱖ130/ⱖ85 mm Hg), the metabolic syndrome can increase the risk for CHD at any LDL cholesterol level. When 3 or more of these risk determinants are present, a diagnosis of the metabolic syndrome can be made. The ATP III guidelines recommend weight loss and physical activity as first-line therapy for the metabolic syndrome. Physical activity reduces levels of verylow-density lipoprotein cholesterol, which contains TG, and increases HDL concentrations. Whereas the ATP III guidelines endorse the use of fibrate drugs or nicotinic acid (ie, niacin) to lower TG levels and increase HDL cholesterol, the ADA notes that nicotinic acid is generally 24S

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contraindicated in individuals with diabetes.21 The ATP III guidelines also state that statins may increase HDL levels by 5% to 15% and reduce TG levels by 7% to 30%. Triglyceride levels ⬍150 mg/dL are considered normal. Although HDL cholesterol levels ⬍40 mg/dL are classified as a major CHD risk factor, the ATP III guidelines do not set a goal for HDL–raising therapy for 2 reasons: insufficient clinical evidence to support a specific goal (although data suggest that increasing HDL reduces risk) and a lack of drugs that robustly increase HDL cholesterol. When low HDL is associated with high LDL cholesterol or TG levels, the emphasis rests on treating the other lipid abnormalities. Pharmacologic intervention aimed specifically at increasing HDL cholesterol should generally be considered when TG levels are ⱕ200 mg/dL (isolated low HDL) and the patient has CHD or a CHD risk equivalent.

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HYPOGLYCEMIC AGENTS FOR LIPID MANAGEMENT IN DIABETES There is growing interest in the role of hypoglycemic agents in preventing or managing insulin resistance and dyslipidemia. Metformin, an insulin-sensitizing drug, has been shown to reduce LDL cholesterol as well as modify other metabolic risk factors for CHD.23 The Diabetes Prevention Program, a study sponsored by the National Institutes of Health, evaluated the effect of intensive lifestyle changes and of metformin on the progression to type 2 diabetes in 3,234 patients with impaired glucose tolerance and a mean age of 51 years.24 Preliminary reports show that intensive lifestyle changes could decrease the risk for developing overt diabetes by 58%. In the group treated with metformin, there was a 31% reduction in the risk for diabetes. The thiazolidinediones, another class of insulin sensitizers, are agonists for the peroxisome proliferator-activated receptor (PPAR)–␥, a nuclear receptor that promotes adipocyte differentiation and lipid storage. Activation of PPAR␥ by drugs of this class can decrease glucose levels and favorably modify lipids.25 However, glycemic control alone has not generally been recognized to prevent macrovascular disease; whether these newer agents will have any impact on CHD risk remains to be seen in clinical trials.

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CONCLUSION The weight of clinical evidence indicates that diabetic patients have a greatly increased risk for CHD, with the previously mentioned East-West study suggesting that diabetes is associated with a CHD event risk comparable to that seen among nondiabetic patients with established CHD.2 The newly revised NCEP guidelines reflect this view, recommending that patients with diabetes receive aggressive treatment even in the absence of clinical coronary disease. Subgroup analyses of primary and secondary prevention trials strongly support the use of lipid modification, including statin and fibrate therapy, in this patient population. It is hoped that results from future clinical trials will help us to individualize treatment strategies for each person with diabetes in order to derive the maximum clinical benefit from lipid-modifying therapy.

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REFERENCES 1. Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes. 1999;48:937–942. 2. Haffner SM, Lehto S, Ro¨ nnemaa T, et al. 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. 3. Alexander CM, Landsman PB, Teutsch SM. Diabetes mellitus, impaired fasting glucose, atherosclerotic risk factors and prevalence of coronary heart disease. Am J Cardiol. 2000;86:897–902. 4. Downs JR, Clearfield M, Weis S, et al, for the AFCAPS/ TexCAPS Research Group. Primary prevention of acute

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coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA. 1998;279:1615–1622. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349 –1357. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996; 335:1001–1009. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–1307. Rubins HR, Robins SJ, Collins D, et al, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of highdensity lipoprotein cholesterol. N Engl J Med. 1999;341: 410 – 418. Watts GF, Dimmitt SB. Fibrates, dyslipoproteinaemia and cardiovascular disease. Curr Opin Lipidol. 1999;10:561– 574. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) Study Group. Circulation. 2000;102:21–27. Koskinen P, Ma¨ntta¨ri M, Manninen V, et al. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care. 1992;15:820 – 825. Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001;357:905– 910. Pyo¨ra¨la¨ K, Pedersen TR, Kjekshus J, et al. 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 S, Alexander CM, Cook TJ, et al, for the Scandinavian Simvastatin Survival Study Group. 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. Sacks FM, Tonkin AM, Shepherd J, et al, for the Prospective Pravastatin Pooling Project Investigators Group. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors. The Prospective Pravastatin Pooling Project. Circulation. 2000;102:1893–1900. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus. Evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001;103:357–362. Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatory cytokine production by pravastatin. Lancet. 1999;353:983–984. THE AMERICAN JOURNAL OF MEDICINE威

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A Symposium: Lipid Management in Diabetic Patients/Gotto, Jr. 19. Yudkin JS, Stehouwer CDA, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction. A potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol. 1999;19:972–978. 20. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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. 21. American Diabetes Association. Position statement. Management of dyslipidemia in adults with diabetes. Diabetes Care. 2002;25(suppl 1):74 –77. 22. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the Second

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Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015–3023. 23. Glueck CJ, Fontaine RN, Wang P, et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism. 2001;50:856 – 861. 24. Knowler WC, Barrett-Connor E, Fowler SE, et al., for the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393– 403. 25. Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem. 2001;70:341–367.

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