(ACCORD) Trial - Semantic Scholar

(ACCORD) Trial - Semantic Scholar

Evolution of the Lipid Trial Protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial Henry N. Ginsberg, MD,a Denise E. Bonds,...

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Evolution of the Lipid Trial Protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial Henry N. Ginsberg, MD,a Denise E. Bonds, MD, MPH,b Laura C. Lovato, MS,c John R. Crouse, MD,d,* Marshall B. Elam, MD, PhD,e Peter E. Linz, MD,f Patrick J. O’Connor, MPH, MD,g Lawrence A. Leiter, MD,h Daniel Weiss, MD, CDE,i Edward Lipkin, MD, PhD,j and Jerome L. Fleg, MD,k for the ACCORD Study Group† The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial aims to test whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) plus a fibrate is more efficacious in reducing cardiovascular events than a statin plus placebo in patients with type 2 diabetes mellitus with defined glycemic control. This is a blinded component in a 5,518-patient subset of the ACCORD cohort. These participants were randomized to either be (1) treated with simvastatin (titrated to 40 mg/day if necessary to achieve a goal low-density lipoprotein [LDL] cholesterol level of <2.59 mmol/L [100 mg/dL]) plus placebo or (2) treated to the same goal LDL cholesterol level with the statin plus active fenofibrate 160 mg/day or its bioequivalent (or 54 mg/day if the estimated glomerular filtration rate ranges from 30 to <50 mL/min per 1.73 m2). Setting an upper limit of LDL cholesterol qualifying for randomization excluded patients who would not likely achieve the LDL cholesterol goal. Recruitment for ACCORD began in January 2001, and follow-up is scheduled to end in June 2009. Since recruitment began, several clinical trials and consensus statements have been published that led to changes in the details of the lipid treatment algorithm and protocol. This report describes the design of the lipid protocol and modifications to the protocol during the course of the study in response to and in anticipation of these developments. The current protocol is designed to provide an ethically justifiable test of combined statin plus fibrate treatment consistent with the highest level of safety and lipid treatment standards of care. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99[suppl]:56i– 67i)

The reduction of cardiovascular risk is the most important goal in the pharmacologic management of dyslipidemia in high-risk populations. Because event rates remain higher in patients with diabetes mellitus than in those without diabetes despite increasingly intensive care, 2 new strategies have been discussed: the reduction of low-density lipoprotein (LDL) cholesterol to a lower concentration than advocated

a

Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA; bDepartment of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USA; cDepartment of Biostatistical Sciences and dDepartment of Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; eDepartment of Medicine, University of Tennessee Health Science Center, and Memphis Veterans Affairs Medical Center, Memphis, Tennessee, USA; fNaval Medical Center San Diego, San Diego, California, USA; gHealthPartners Research Foundation, Minneapolis, Minneapolis, USA; hDepartment of Medicine, University of Toronto, St. Michael’s Hospital, Toronto, Ontario, Canada; i Your Diabetes Endocrine Nutrition Group, LLC, Mentor, Ohio, USA; and jDivision of Nutrition, Metabolism & Endocrinology, Department of Medicine, University of Washington, Seattle, Washington, USA; and k Atherothrombosis and Coronary Artery Disease Branch, Division of Cardiovascular Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.03.024

in the current guidelines and the treatment of high-density lipoprotein (HDL) cholesterol and triglycerides in addition to LDL cholesterol. The former strategy has been and is being tested in several clinical trials, but the latter has not previously been tested. For this reason, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial investigators developed a protocol for the lipid component of the overall ACCORD trial to answer the following question: In the context of good glycemic control, does a therapeutic strategy that uses a fibrate to increase HDL This work was supported by Contract Nos. N01-HC-95178, N01-HC95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA #Y1-HC-9035, and IAA #Y1-HC-1010 from the National Heart, Lung, and Blood Institute (NHLBI), with additional support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute (NEI), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention (CDC). General Clinical Research Centers provide support at many sites. *Address for reprints: John R. Crouse, MD, Department of Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston Salem, North Carolina 27157. E-mail address: [email protected] † A complete list of the names and affiliations of members of the ACCORD Study Group appears in the Appendix. www.AJConline.org

Ginsberg et al/ACCORD Lipid Trial

cholesterol and lower triglyceride levels together with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) to lower LDL cholesterol reduce the rate of cardiovascular disease (CVD) events compared with a strategy that uses a statin plus a placebo? This report presents the rationale, initial ACCORD lipid trial design, and modifications to the design of the lipid protocol during the first 3.5 years of the trial in response to new knowledge and changes in guidelines for lipid management.

Background: Overall Action to Control Cardiovascular Risk in Diabetes Design and the Lipid Trial Component Details regarding the overall rationale and design of ACCORD in general can be found elsewhere in this supplement.1,2 Briefly, the overall goal of the ACCORD trial is to test 3 complementary medical treatment strategies for reducing the rate of major CVD morbidity and mortality in type 2 diabetes mellitus. It was designed as a randomized, multicenter, double 2 ⫻ 2 factorial trial in 10,000 patients with type 2 diabetes. Ultimately, 10,251 participants were recruited. The trial is designed to test the effects on preventing major CVD events of intensive glycemic control, treatment to increase HDL cholesterol and lower triglycerides (in the context of good LDL cholesterol and glycemic control), and intensive blood pressure control (in the context of good glycemic control). All 10,251 participants are in the glycemia trial. In addition, one 2 ⫻ 2 trial will address the blood pressure question in 4,733 of the recruited participants, while the other 2 ⫻ 2 trial will address the lipid question in 5,518 of the participants. Therefore, each participant will be in a 2 ⫻ 2 trial testing 2 treatment strategies of 2 interventions, one of which is always glycemic control and the other is either lipid or blood pressure control. The lipid component is the only masked portion of the trial. The primary outcome measure for each part of ACCORD is the first occurrence of a major CVD event, specifically nonfatal myocardial infarction (MI) or stroke or cardiovascular death. Participants were recruited over 2 noncontiguous periods (the vanguard phase and the main trial), and follow-up is planned for about 4 – 8 years (approximate mean, 5.6 years).2

Rationale for the Action to Control Cardiovascular Risk in Diabetes Lipid Hypothesis The design of ACCORD began in 1999. The guidelines for the management of dyslipidemia at the time were the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) II.3 These 1993 guidelines considered LDL cholesterol as the cornerstone of lipid management, but by 1999, they were outdated. In particular, the ATP II guidelines were formulated before the publication of results

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of the major statin trials, and they identified bile acid– binding resins as the drugs of first choice for the management of elevated LDL cholesterol. In addition, ATP II stratified risk (for people free of CVD) on the basis of adding together the number of risk factors a person possessed rather than identifying people with multiple risk factors and then stratifying risk factors according to their severity (as the 2001 update of these guidelines, ATP III, recommended).4 In ATP II, diabetes was one of the important risk factors (along with smoking, hypertension, age, sex, and HDL cholesterol) but was not considered as important a risk factor for CVD as prevalent vascular disease per se (coronary, cerebral, or peripheral vascular disease). ATP II defined the treatment initiation level and target level of LDL cholesterol for patients with vascular disease as 3.36 mmol/L (130 mg/dL) and ⱕ2.59 mmol/L (ⱕ100 mg/dL), respectively. There was a “gray zone” for LDL cholesterol of 2.59 –3.36 mmol/L (100 –130 mg/dL), for which management was left up to clinicians. During the ACCORD planning phase, it was known that a revision of the guidelines was under way and that, most importantly, statins were the first-line agents for the management of elevated LDL cholesterol, as a result of the Scandinavian Simvastatin Survival Study (4S), the Cholesterol and Recurrent Events (CARE) trial, the Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) trial, the West of Scotland Coronary Prevention Study (WOSCOPS), and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)—landmark clinical trials that established their efficacy for the reduction of cardiovascular events and their safety and tolerability.5–9 New data from the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) study also supported the use of fibrates for the reduction of coronary artery disease (CAD) events and stroke10 and confirmed previous results of the Helsinki Heart Study (HHS).11 In addition, it was anticipated that the ATP III guidelines would suggest lower thresholds for the treatment of LDL and would consider diabetes as a CAD “risk equivalent.” Several concerns remained, however, even with implementation of the ATP III guidelines for the management of dyslipidemia in high-risk populations. For example, cardiac event rates in the actively treated groups of 4S, CARE, and LIPID remained at a very high level of ⱖ20% every 10 years, even in populations with effective statin treatment to a mean LDL cholesterol level of about 2.59 mmol/L (100 mg/dL). This was particularly evident in the subsets of effectively treated patients with diabetes in these trials, in whom event rates ranged from 31%–58% every 10 years. Similarly, despite marked reductions in events with fibrate management, cardiac event rates remained high in the active treatment group of the insulin-resistant subset of VA-HIT.12 Thus, during the development of the ACCORD lipid protocol, 2 strategies were considered that might further reduce these high event rates in a high-risk population: (1) the further reduction of LDL cholesterol beyond the

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ATP III target of ⬍2.59 mmol/L (100 mg/dL) and (2) combination treatment using a statin and a second agent (niacin or a fibrate) that would lower serum concentrations of triglyceride and increase HDL cholesterol. Because it was known in 1999 that the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT), the Treating to New Targets (TNT) trial, the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) trial would provide answers to the question of the efficacy and safety of a targeted LDL cholesterol level ⬍2.59 mmol/L (100 mg/dL),13–16 the ACCORD investigators thought that it was more important to test combination therapy than intensive LDL cholesterol lowering beyond the level specified by the guideline then in force (⬍2.59 mmol/L [100 mg/dL]). The question of the relative efficacy of combination therapy was compelling for 2 reasons: (1) the relative risk versus benefit of combination therapy was not defined in a population with diabetes that characteristically presented with high triglycerides and low HDL cholesterol but in whom LDL cholesterol concentrations were typically either no different or mildly elevated compared with patients without diabetes and (2) only the Lipids in Diabetes Study (LDS)17 was known to have initiated a test of combined therapy for the reduction of cardiovascular events. The LDS was designed and initiated as a 2 ⫻ 2 factorial trial of fenofibrate and cerivastatin over 5 years in 5,000 patients with type 2 diabetes but was stopped early because of concerns about the toxicity of cerivastatin. A fibrate rather than niacin was selected as the drug to be tested in ACCORD, because VA-HIT and HHS had shown benefits of fibrate in populations with overrepresentation of diabetes and the metabolic syndrome. Also, there was concern that even the small reductions in insulin sensitivity accompanying niacin therapy18 would make it more difficult to achieve intensive glycemic control in the overall glycemic trial. It was also necessary to address the safety of fibrate use in the setting of statin treatment, because the potential for increased myopathy with combination therapy (particularly the combination of statin with gemfibrozil) was well recognized. Ultimately, fenofibrate and simvastatin were chosen as the fibrate and statin for the trial. The choice of fenofibrate rather than gemfibrozil as the study medication proved fortuitous insofar as it has been subsequently demonstrated that a significant pharmacodynamic interaction exists between gemfibrozil (but not fenofibrate) and simvastatin (see the following discussion).

Evolution of the Action to Control Cardiovascular Risk in Diabetes Lipid Protocol As noted previously, recruitment and follow-up for ACCORD was divided into a vanguard phase (January 2001

to December 2002) and a main trial phase (February 2003 to June 2009). The vanguard phase evaluated recruitment and treatment strategies for all components of the trial, including the lipid component, before the institution of the full trial. Lessons learned from the vanguard phase were incorporated into the main trial protocol. Protocol changes in lipid trial eligibility and treatment made from the initiation of the trial through the present are listed in Table 1. Vanguard phase protocols (January 2001 to December 2002): To test the hypothesis that a fibrate plus a statin is more efficacious than a statin alone in reducing CVD events without compromising safety, it was decided at the beginning of the vanguard phase that all participants in the lipid component would be treated with unblinded simvastatin to a minimal LDL cholesterol goal of ⬍3.36 mmol/L (130 mg/dL) but that the study would randomly assign participants to fenofibrate or its placebo in a blinded fashion. There were 2 important questions regarding the implementation of this design: (1) How could the study ensure that participants medicated with a variety of statins and doses of statins at baseline would achieve acceptably low LDL cholesterol levels with simvastatin? (2) How would the study ensure the safety of the combination therapy in light of the known potential side effects of the drugs in combination? In addition, the ACCORD investigators recognized the need to deal with the possibility that a small number of patients might become refractory to treatment and develop serum concentrations of LDL cholesterol and triglycerides greater than the levels the guidelines then recommended. This necessitated incorporating into the protocol an option for titration of the statin. Although the ACCORD investigators understood that the ATP III guidelines would continue to recommend an LDL cholesterol treatment initiation level of ⬎3.36 mmol/L (130 mg/dL) for high-risk patients, a lower threshold was chosen in ACCORD to enhance the cardiac protection of the statin, specifically ⬎3.10 mmol/L (120 mg/dL). For the vanguard phase, the protocol called for a maximum dose of simvastatin of 20 mg/day for safety (see the following discussion) and developed a titration algorithm with doses of 0 – 20 mg/day for those patients with LDL cholesterol ⬎3.10 mmol/L (120 mg/dL). Because patients with LDL cholesterol ⬎4.40 mmol/L (170 mg/dL) would require doses of simvastatin ⬎20 mg/day to achieve an LDL cholesterol level ⬍2.59 mmol/L (100 mg/dL), they were not eligible for the ACCORD lipid component.2 Because such high LDL cholesterol levels are uncommon in patients with diabetes, the ACCORD investigators anticipated that this criterion would not exclude many from the trial. With this approach, it was estimated that patients with up to the highest allowable baseline LDL cholesterol levels (4.40 mmol/L [170 mg/dL]) would achieve an LDL cholesterol level of approximately 2.84 mmol/L (110 mg/dL), assuming a 35% reduction in LDL cholesterol in those participants treated with simvastatin 20 mg/day. This titration algorithm attempted to

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Table 1 Changes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid protocol over time* Protocol Element

Vanguard Phase (January 2001–December 2002)

Main Trial (Went into Effect January 2003)

10/16/00 Protocol

9/13/01 Protocol

11/14/02 Protocol

8/31/04 Protocol

5/11/05 Protocol

LDL-C eligibility criterion HDL-C eligibility criterion

ⱕ170 mg/dL ⬍50 mg/dL

Same Same

85–170 mg/dL Same

Same Same

Starting dose of statin

0 if LDL-C ⬍116 mg/dL 5 mg/day if LDL-C 116–150 mg/dL 10 mg/day if LDL-C 151–170 mg/dL Initial 120 mg/dL Subsequent 130 mg/dL

Same

All 20 mg/day No titration

60–180 mg/dL ⬍55 mg/dL, women or African American; ⬍50 mg/dL all others All 20 mg/day to start except ppts with CVD ⫽ 40 mg/day

120 mg/dL for all

No titration

Uptitrate to 40 mg/day if LDL ⬎100 mg/dL ⫻2 If ⬎120 mg/dL ⫻ 2 and on 40 mg/day statin, D/C blinded medications/transfer Same

LDL-C level for statin uptitration

LDL-C alert: D/C study medications

If 130 mg/dL ⫻ 2 and on maximum statin dose, D/C blinded medications/transfer

Same

Same

Triglyceride alert

Same

Same

Downtitrate statin

If ⬎750 mg/dL ⫻ 2, D/C blinded medications/transfer ⬍50 mg/dL

Same

Fibrate dose

160 mg/day

Same

If ⬍40 mg/dL ⫻ 2, D/C statin Same

Same

Same, with addition to uptitrate to 40 mg/ day if ppt has CVD event Same

Same

Same

Same

54 or 160 mg/day (or bioequivalent doses) based on GFR

Same

CVD ⫽ cardiovascular disease; D/C ⫽ discontinue; fibrate ⫽ fenofibrate; GFR ⫽ glomerular filtration rate estimated by the Modified Diet in Renal Disease equation (see text for details); HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol; ppt ⫽ participant; statin ⫽ simvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor); transfer ⫽ transferring this aspect of patient care back to participant’s private physician. * For HDL-C and LDL-C, 1 mg/dL ⫽ 0.02586 mmol/L. † For triglyceride, 1 mg/dL ⫽ 0.01129 mmol/L.

reach appropriate LDL cholesterol goals while using the lowest efficacious dose of simvastatin in combination with a fibrate. The initial dose of simvastatin was tailored to the participant’s observed (or estimated; see the following discussion) baseline LDL cholesterol level (Table 1). For participants whose LDL cholesterol was ⬍2.97 mmol/L (115 mg/dL), no treatment was initiated. For those with LDL cholesterol of 3.00 –3.88 mmol/L (116 –150 mg/dL), simvastatin therapy was initiated at 5 mg/day. For those with LDL cholesterol ⬎3.88 mmol/L (150 mg/dL) to ⱕ4.40 mmol/L (170 mg/dL), simvastatin 10 mg/day was initiated. If on repeat testing LDL cholesterol was ⬎3.10 mmol/L (120 mg/dL), the dose of simvastatin was increased to a maximum of 20 mg/day. If a patient’s LDL cholesterol level was consistently ⬎3.36 mmol/L (130 mg/dL) on subsequent testing, the simvastatin and blinded medication were permanently stopped, and the patient was referred to his or her primary care physician for appropriate treatment. (Although the participant was no longer taking the ACCORD lipid medications, he or she continued to be treated in the glycemia trial and was followed for events.) In a slight revision

to the lipid protocol in September 2001, and to minimize confusion in clinics, the LDL cholesterol threshold for uptitration was standardized to 3.10 mmol/L (120 mg/dL) only (Table 1). To include patients in the trial who were taking lipidlowering medications at baseline and not have to wash out clinically indicated medications, an algorithm was developed that used the measured on-treatment LDL cholesterol level together with the expected percentage reduction of LDL cholesterol resultant from the pretrial drug and dose to estimate the LDL cholesterol level that would have been caused by discontinuing the treatment. This is listed in Table 2. If the estimated “off-treatment” LDL cholesterol level was ⬍4.40 mmol/L (170 mg/dL), the patient was LDL eligible for randomization, and the dose of simvastatin provided was that appropriate for the patient’s estimated LDL cholesterol, as described previously. AFCAPS/TexCAPS (with a statin)9 and VA-HIT (with a fibrate)10 had shown the efficacy of pharmacologic management in subsets of the populations with low HDL cholesterol concentrations. In ACCORD, to select a population of patients at increased risk for CVD due to low HDL choles-

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Table 2 Low-density lipoprotein cholesterol (LDL-C) eligibility ranges for screenees taking lipid-lowering agents (by agent and dose), from November 21, 2003, protocol Lipid-Lowering Agent

Atorvastatin Atorvastatin Atorvastatin Atorvastatin Atorvastatin Atorvastatin Simvastatin Simvastatin Simvastatin Simvastatin Simvastatin Lovastatin Lovastatin Lovastatin Lovastatin Pravastatin Pravastatin Pravastatin Pravastatin Fluvastatin Fluvastatin Rosuvastatin Rosuvastatin Rosuvastatin Rosuvastatin Rosuvastatin Ezetimibe Fenofibrate Niacin Resin All others

Dose (mg)

2.5 5 10 20 40 80 5 10 20 40 80 10 20 40 80 10 20 40 80 20 40 5 10 20 40 80 10 Any Any Any Any

Estimated % LDL-C Reduction

25 29 39 43 50 60 26 30 38 41 47 18 24 30 40 22 32 34 40 22 24 40 46 52 55 58 17 5 10 10 0

LDL-C Eligibility Range (Inclusive) mg/dL

mmol/L

64–128 60–121 52–104 48–97 43–85 34–68 63–126 60–119 52–105 50–100 45–90 70–139 65–129 60–119 51–102 66–133 58–116 56–112 51–102 66–133 65–129 51–102 46–92 41–82 38–77 36–71 71–141 81–162 77–153 77–153 85–170

1.65–3.30 1.56–3.12 1.34–2.68 1.25–2.51 1.10–2.20 0.88–1.76 1.63–3.25 1.54–3.08 1.36–2.73 1.30–2.59 1.17–2.33 1.80–3.60 1.67–3.34 1.54–3.08 1.32–2.64 1.72–3.43 1.50–2.99 1.45–2.90 1.32–2.64 1.72–3.43 1.67–3.34 1.32–2.64 1.19–2.37 1.06–2.11 0.99–1.98 0.92–1.85 1.83–3.65 2.09–4.18 1.98–3.96 1.98–3.96 2.20–4.40

Reflects the off-treatment LDL-C entry criterion of 85–170 mg/dL (2.20 – 4.40 mmol/L), later altered by the August 31, 2004, protocol, which broadened LDL-C entry criteria to 60 –180 mg/dL (1.55– 4.65 mmol/L).

terol, who would likely benefit most from HDL increases, patients whose HDL cholesterol was ⱖ1.29 mmol/L (50 mg/dL) were excluded during the vanguard phase (Table 1). In addition, patients were excluded if their serum concentrations of fasting triglycerides were ⬎8.47 mmol/L (750 mg/dL) (⬎4.52 mmol/L [400 mg/dL] if receiving fibrate or niacin treatment), because such patients would be at increased risk for developing pancreatitis as a result of uncontrolled hypertriglyceridemia if randomized to placebo rather than fenofibrate. Safety of combination therapy: At the time of the development of the ACCORD lipid trial’s vanguard protocol, the scientific community had considerable concern about the combined use of a statin and a fibrate.3,4 This concern was reinforced (and the importance of the proposed study design heightened) toward the end of the vanguard phase, when Bayer (Leverkusen, Germany) withdrew cerivastatin from the market (and thus terminated the LDS prematurely) because of an excess of episodes of rhabdomyolysis in the community at large, particularly when it was used in con-

junction with gemfibrozil (August 2001).19,20 Thus, assurance of the safety of the combination of simvastatin and fenofibrate was of great importance. To this end, the investigators decided that the maximum dose of simvastatin should be 20 mg/day. To ensure patient safety, the frequency and severity of muscle symptoms were monitored at every clinic visit, and creatine phosphokinase (CPK) concentrations were measured at baseline, 4 months, 8 months, 12 months, and annually thereafter and as needed for moderate to severe unexplained muscle symptoms. Through the ACCORD Data and Safety Monitoring Board (DSMB), the frequency and severity of reported muscle symptoms and the frequency of CPK elevations with and without symptoms were monitored by treatment group. Also, patients were withdrawn from lipid-lowering therapy for CPK ⬎10 times the upper limit of normal in the absence of symptoms or for CPK ⬎5 times the upper limit of normal in the presence of symptoms. In addition, simvastatin therapy was to be avoided in participants who developed myositis while taking blinded medication.

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As another safety measure, if the triglyceride level was ⬎8.47 mmol/L (750 mg/dL) on 2 consecutive visits (even after adherence review and dietary counseling), the 2 lipid medications (simvastatin and the blinded medication) were stopped, and again, the participant’s private physician was notified so that appropriate private lipid-lowering therapy might be initiated. Also, if a patient’s LDL cholesterol became ⬍1.29 mmol/L (50 mg/dL), the statin dose was titrated down by 50%, because the safety of very low levels of LDL cholesterol has not been clearly established. Main trial protocols (January 2003 to the present)— changes necessitated by new evidence: The results of the Medical Research Council/British Heart Foundation (MRC/ BHF) Heart Protection Study (HPS) were reported in July 2002.21 This was a randomized, double-blind, placebo-controlled clinical trial testing whether simvastatin 40 mg/day reduced the risk for all-cause mortality and cardiovascular events in 20,536 high-risk patients (including 5,963 with diabetes)22 treated over 5 years. The low baseline total cholesterol exclusion criterion (⬎3.49 mmol/L [135 mg/dL]) resulted in enrollment of many patients with LDL cholesterol concentrations ⬍2.84 mmol/L (110 mg/dL). Most importantly, the HPS showed that simvastatin reduced clinical events by about 25%, even in participants with baseline LDL cholesterol ⬍2.59 mmol/L (100 mg/dL). The results of the HPS, together with the complexity of the statin treatment in the vanguard phase, led the ACCORD investigators to eliminate statin titration from the main trial and postvanguard portion of the trial and to treat all participants with simvastatin 20 mg/day (Table 1). That is, no participants were left untreated with the statin. This strategy necessitated a change in the eligibility criteria, because if all patients were to be treated with simvastatin 20 mg, it was necessary to protect patients from reductions in LDL cholesterol concentrations to unacceptably low levels. In the revision of the protocol adopted on November 14, 2002, a lower inclusion level for LDL cholesterol of 2.20 mmol/L (85 mg/dL) was adopted. Furthermore, the statin was discontinued if LDL cholesterol decreased to ⬍1.03 mmol/L (40 mg/dL); blinded fibrate or fibrate placebo could be continued. In April 2004, the results of PROVE-IT–TIMI 22 were reported.13 This was a randomized, blinded clinical trial that compared the 2-year cardiovascular event rate caused by an aggressive LDL-lowering strategy (atorvastatin 80 mg/day, on-treatment LDL cholesterol 1.60 mmol/L [62 mg/dL]) with that caused by a less aggressive strategy (pravastatin 40 mg/ day, LDL cholesterol 2.46 mmol/L [95 mg/dL]) in the setting of an acute coronary event (acute MI or high-risk unstable angina) within the preceding 10 days.13 In this very high risk population (20% event rate in the first year), there was a 16% reduction in the hazard ratio favoring the more aggressive strategy (p ⫽ 0.005). However, this trial did not show that the achievement of a marked reduction in LDL cholesterol was superior to the achievement of the ATP III prescribed

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guideline of ⬍2.59 mmol/L (100 mg/dL), because the less aggressively managed group was not titrated to an LDL cholesterol goal of ⬍2.59 mmol/L (100 mg/dL). The results of PROVE-IT–TIMI 22 supported the recommendations of the ATP III “implications” report of July 2004, which suggested that, for patients at “very high risk,” including those with acute coronary events and those with diabetes combined with coronary disease, an optional LDL cholesterol goal of ⬍1.81 mmol/L (70 mg/dL) could be considered.23 Subsequently, the TNT trial confirmed the benefit of achieving a target LDL cholesterol level ⬍2.59 mmol/L (100 mg/dL) (mean on-treatment LDL cholesterol 1.99 mmol/L [77 mg/dL]) rather than a target of 2.59 mmol/L (100 mg/dL) in patients with coronary disease.14 These studies and recommendations increased the pressure to achieve lower LDL cholesterol levels in ACCORD and increased sensitivity to the importance of lowering LDL cholesterol to ⬍2.59 mmol/L (100 mg/dL). Another important development was the observation of differences between fibrates in their pharmacologic interactions with statins. Whereas the coadministration of gemfibrozil with various statins increased the area under the statin serum concentration curve, no such effect was observed when fenofibrate was coadministered with a statin.20 This difference has been demonstrated to be caused by the inhibition of acid glucuronidation of statins by gemfibrozil.24 This body of research lessened concern that the coadministration of simvastatin with fenofibrate would result in excess muscle adverse events. The conjunction of evidence that patients at high risk should achieve LDL cholesterol ⬍2.59 mmol/L (100 mg/ dL) and that the combination of fenofibrate with a statin possibly posed no greater risk than expected from the additive effects of either drug alone, together with the safety experience with the combination of fenofibrate and simvastatin 20 mg in the vanguard phase and early phase of the main trial, prompted the ACCORD investigators to modify the lipid management strategy (August 2004 protocol) so that simvastatin should be titrated up to 40 mg if the LDL cholesterol level remained consistently ⬎2.59 mmol/L (100 mg/dL) (Table 1). (Extending this notion of who should be taking simvastatin 40 mg, the May 2005 protocol mandated that all secondary prevention participants in the lipid trial should also receive this higher dose.) Given that a strategy was in place for the discontinuation of the statin if LDL cholesterol decreased to ⬍1.03 mmol/L (40 mg/dL), the inclusion criteria for trial eligibility were also broadened in August 2004 to include patients with LDL cholesterol of 1.55– 4.65 mmol/L (60 –180 mg/dL). It is expected that this algorithm for simvastatin treatment will provide an average LDL cholesterol in the lipid portion of ACCORD that will be well below 2.59 mmol/L (100 mg/dL) and that only a very small percentage of patients will have LDL cholesterol concentrations ⬎2.59 mmol/L (100 mg/dL). Additionally, the protocol was changed in August 2004 so that an LDL cholesterol level

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⬎3.10 mmol/L (120 mg/dL) with simvastatin 40 mg would lead to the discontinuation of the blinded medication and the transfer of care to the patient’s private physician for the appropriate therapy for LDL cholesterol. Another modification of the protocol dealt with a slight elevation of serum creatinine levels associated with fenofibrate use. After observing that some lipid trial participants had experienced increases in serum creatinine after randomization to blinded fenofibrate or placebo therapy, the ACCORD investigators noted published research suggesting an association of uncertain significance between fenofibrate use and increases in serum creatinine concentrations.25,26 At least 1 report suggested that the increase in creatinine associated with fenofibrate use was not associated with a deterioration of renal function, and the effect was determined to be rapidly reversible.26 However, in the course of researching this question, the manufacturer’s recommendation that the dose of fenofibrate be reduced or discontinued in patients with impaired renal function was noted, and for the purpose of safety and to avoid the accumulation of metabolites, the protocol was changed in August 2004 so that the dose of blinded medication was to be titrated down on the basis of the patient’s estimated glomerular filtration rate (GFR). Specifically, the fenofibrate (or matching placebo) dose is titrated to 54 mg/day if the estimated GFR consistently ranges from 30 to ⬍50 mL/min per 1.73 m2 and discontinued if the estimated creatinine clearance is consistently ⬍30 mL/min per 1.73 m2. Finally, to increase the numbers of women and minorities in the study, and recognizing that women and African Americans with diabetes tend to have CVD despite higher HDL cholesterol concentrations than others, the entry HDL cholesterol criteria were changed so that women or African Americans with HDL cholesterol ⬍1.42 mmol/L (55 mg/dL) were eligible for the study, whereas all others were required to have HDL cholesterol ⬍1.29 mmol/L (50 mg/dL).

Conclusion One of the most important questions that could be asked about the pharmacologic management of dyslipidemia in patients with diabetes is whether combined therapy with a statin plus a fibrate offers an additional reduction of cardiovascular events beyond that of a statin alone, with an acceptable risk profile. The importance of this question is highlighted by the recent Simvastatin Plus Fenofibrate for Combined Hyperlipidemia (SAFARI) trial, evaluating lipid responses and the safety of combination therapy as opposed to a statin alone.27 This study showed a statistically significant benefit of the combination therapy in reducing LDL cholesterol and triglycerides and increasing HDL cholesterol with similar clinical, muscular, and liver adverse experiences over 12 weeks in 619 patients with combined hyperlipidemia. ACCORD will address these issues, as

well as the issue of clinical outcomes in patients with diabetes. The original design of the lipid component of ACCORD was made after considerable deliberation. However, during the first 5 years of the trial, the results of several major clinical trials, including HPS,21 PROVE-IT–TIMI 22,13 and TNT,14 and expert lipid panelists’ recommendations (NCEP ATP III,4 Grundy et al23) led to significant modifications in the ACCORD lipid trial study design. In addition, there were 2 important developments relating specifically to the use of fenofibrate in the trial. One supported the greater safety of fenofibrate than gemfibrozil when used in association with a statin,20 and another highlighted an association of uncertain significance of increasing serum creatinine associated with fenofibrate use.25,26 Related to this last point are the observations reported in 2005 from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, which compared fenofibrate therapy with placebo (in the absence of specifically mandated LDL cholesterol–lowering therapy) in 9,795 patients with type 2 diabetes to assess the effect of the fibrate on CVD events.28 In that trial, although an 11% reduction in total cardiovascular events (a secondary outcome; p ⫽ 0.035) was observed, it was also noted that during the course of the 5-year trial, median plasma creatinine levels remained about 11 ␮mol/L (0.1 mg/dL) higher in the fenofibrate group compared with the placebo group. In a subset of patients restudied 8 weeks after the discontinuation of the study medication, the median plasma creatinine in the fenofibrate participants decreased to a level observed in those assigned placebo.28 The ACCORD investigators were sensitive to the clinical implications of these developments and revised the protocol accordingly. In each case, the potential benefit of a modification of the treatment regimen was balanced against the potential toxicity of the combination of a statin and a fibrate. Overall, ACCORD has been able to proceed through several iterations of the original lipid trial design. The current study protocol meets the standards of present optimal care on the basis of evidence from clinical trials, without jeopardizing our ability to detect differences in important outcomes. Of obvious concern at every step of protocol revision is the effect of protocol change on the power of the trial to answer the research questions. This applies to the smaller lipid trial and the overarching glycemia trial. However, the changes that have been made from the first vanguard protocol (October 2000) to the current protocol (May 2005) have not had any large effect on power. Specifically, it was stated in the October 2000 protocol that the glycemia trial had 92% power and the lipid trial had 90% power to answer their respective questions. In the May 2005 protocol, these had been reduced to 89% and 87%, respectively. The designs of major clinical trials of long durations are likely to be significantly affected by changes in knowledge and treatment recommendations over the life of the trials, as evident from ACCORD. Sponsors of such trials should

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anticipate the need for changes in the protocols in response to evolving evidence, which will have significant operational implications in terms of budgets, the need for periodic updating of patient consent, and the power of large trials to test their prespecified hypotheses. 1. Goff DC, Gerstein HC, Ginsberg HN, Cushman WC, Margolis KL, Byington RP, Buse JB, Genuth S, Probstfield JL, Simons-Morton DG, for the ACCORD Study Group. Prevention of cardiovascular disease in persons with type 2 diabetes mellitus: current knowledge and rationale for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol 2007;99(suppl):4i–20i. 2. ACCORD Study Group. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007; 99(suppl):21i–33i. 3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second 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. 4. 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. 5. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 6. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E, 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. 7. 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. 8. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ, 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. 9. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS [Air Force/ Texas Coronary Atherosclerosis Prevention Study]. JAMA 1998;279: 1615–1622. 10. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, 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 high-density lipoprotein cholesterol. N Engl J Med 1999;341:410 – 418. 11. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317:1237–1245.

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12. Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB, Anderson JW, Collins D, for the Veterans Affairs HDL Intervention Trial (VA-HIT). Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care 2003;26:1513–1517. 13. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–1504. 14. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–1435. 15. MacMahon M, Kirkpatrick C, Cummings CE, Clayton A, Robinson PJ, Tomiak RH, Liu M, Kush D, Tobert J. A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Nutr Metab Cardiovasc Dis 2000;10: 195–203. 16. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Palmer G, for the Incremental Decrease in End Points Through Aggressive Lipid Lowering Study Group. Design and baseline characteristics of the Incremental Decrease in End Points Through Aggressive Lipid Lowering study. Am J Cardiol 2004;94:720 –724. 17. Steiner G. Lipid intervention trials in diabetes. Diabetes Care 2000; 23(suppl):B49 –B53. 18. Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C, Egan D, Kostis JB, Sheps DS, Brinton EA. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT [Arterial Disease Multiple Intervention Trial] study: a randomized trial. JAMA 2000;284:1263– 1270. 19. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 2002;346:539 –540. 20. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol 2004;94:935–938. 21. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360: 7–22. 22. Collins R, Armitage J, Parish S, Sleigh P, Peto R, for the Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361: 2005–2016. 23. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ, for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. J Am Coll Cardiol 2004;44:720 –732. 24. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 2002;30:1280 –1287. 25. Hottelart C, El Esper N, Rose F, Achard JM, Fournier A. Fenofibrate increases creatininemia by increasing metabolic production of creatinine. Nephron 2002;92:536 –541. 26. Hottelart C, el Esper N, Achard JM, Pruna A, Fournier A. Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patients with mild renal insufficiency [in French]. Nephrologie 1999;20:41– 44. 27. Grundy SM, Vega GL, Yuan Z, Battisti WP, Brady WE, Palmisano J. Effectiveness and tolerability of simvastatin plus fenofibrate for com-

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bined hyperlipidemia (the SAFARI trial). Am J Cardiol 2005; 95:462– 468. 28. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, et al, for the FIELD Study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849 –1861.

Appendix The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group: Steering Committee: (Chair) William T. Friedewald, (Vice Chair) John B. Buse, J. Thomas Bigger, Robert P. Byington, William C. Cushman, Saul Genuth, Hertzel C. Gerstein, Henry N. Ginsberg, David C. Goff, Jr, Richard H. Grimm, Jr, Jeffrey L. Probstfield, Denise G. Simons-Morton. Clinical center networks (CCNs) and clinical sites: Canadian CCN: Population Health Research Institute, Hamilton General Hospital, Canadian Diabetes Outcome Researchers (CANDOR Network), Hamilton, Ontario, Canada: Hertzel C. Gerstein, Rosalie Russo, Kim Thompson, Tali Cukierman-Yaffe, Amiram Gafni, Igor Shamis,* Nada Shehadeh, Beth Tadeson,* Vijay Vasudeva, Salim Yusuf. Canadian clinical sites: McMaster Medical Centre, Hamilton, Ontario, Canada: Zubin Punthakee, Sarah Capes,* Priya Manjoo,* Ada Smith, Irene Stanton, Teresa Valla, Susan Danby, William Harper, Patricia Harvey, Dereck Hunt, Audrey Moroso, Rose Otto, Ally Prebtani. Six Nations Health Services, Ohsweken, Ontario, Canada: Zubin Punthakee, Sarah Capes,* Albertha (Bonnie) Davis, Karen L. Hill, Viola (Honey) McCarthy. Diabetes, Hypertension and Cholesterol Centre, University of Calgary, Calgary, Alberta, Canada: Alun L. Edwards, Mary Ann Clearwaters, Diana J. Mitchell, Bob Hammond, Holly Jensen, Armin Kherani, David Lau, Doreen Rabi, Carrie Smith,* Martina Walker, Geoff Williams. Memorial University of Newfoundland, St. John’s, Newfoundland, Canada: Carol Joyce, Minnie Parsons, Bernadette Rowe, Daisy Gibbons,* Jennifer Burton,* Vikram Chandurkar, Susan Coady-McDonald,* Christopher Kovacs, Brad Murphy, Reg Smart, Suja Varghese. University of Alberta, Edmonton, Alberta, Canada: Laurie Mereu, Edmond Ryan, Peter Senior, Judy Germsheid,* Patricia Kirkland, Patricia Werbiski-Wood, Shefina Mawani, Janice Abe,* Ken Dalton, Andrea Jeffrys,* Colin MacDonald, Neelam Makhani, Breay Paty, Mary Pick,* Bernd Schwanke, Matthew Tennant, Sonya Varma, Wanda Zimmerman.* Centre de Recherche Clinique de Laval, Laval, Quebec, Canada: Andre Belanger, Sylvie Gauthier, Josee Girouard, Micheline Labbe, Janie Raymond, Georges Bahsali, Christiane Barbeau, Elaine Caponi, Raymond Duchesne, Richard Dumas, Nicolas Kandalaft, Jean Palardy, Maurice Pilon, Alicia Schiffrin. St. Joseph’s Health Care London, London, Ontario, Canada: Irene Hramiak, Marsha Driscoll, Melissa Gehring, Sue Tereschyn, Grace Walsh, John Gonder, Christopher Lincoln, Charlotte MacDonald, Tom MacDonald, Wanda McBeth, Terri Paul, Pat Pauli, Sharon Powers,* Nicole Ronald, Van Trinh. Ottawa Hospital, Division of Endocrinology and Metabolism, Ottawa, Ontario, Canada: Ron Sigal, Colleen Gilchrist, Julie Maranger, Martha McLean, Tina Leech, Karen Jay,* Rosario Bate, Leah Bradley, Ralph Buhrmann, Brittany Hanlon, Heather Lochnan, Elaine Parker. Royal Victoria Hospital, Montreal, Quebec, Canada: Jean-Francois Yale, France Bouchard, Angela Lombardo, Nancy Renouf, Mylene Roy, Shari A. Segal, Heidi E. Staples, Nathalie Al-

laire,* Isabelle Delpech,* Stephanie Fortin,* Sian Horan,* Mahmoud A. M. A. Alawadhi, David W. Blank, Bonnee Belfer,* Stephanie Buoy-Phang,* Joannie Carter, Lorna Coppin,* Denise Dalpe,* Patrick M. Doran, Francine Emmian,* Natasha Garfield, Marjolaine Gosselin, Maria Kalergis,* Sarantis Koutelias, Jose A. Morais, Michael Ouigley, Nathalie Renouf, Chantale Riopel, Steven Riopel, Juan A. Rivera, Gisele Rochon, Mark H. Sherman, Milva Salera, Mary Shingler, Louise Ulyatt,* Zeina Yared.* St. Michael’s Hospital Health Centre, Toronto, Ontario, Canada: Lawrence A. Leiter, Danielle C. Bedard, Leslie A. Berndl, Gillian Booth, Haysook Choi, Julie A. Kalas, Lisa Sparrow, Alan Berger, Alice Cheng,* Vladimir Evalmplev, Jeannette Goguen, Amir Hanna, Robert G. Josse, Malcolm Pike. Vancouver General Hospital, Vancouver, British Columbia, Canada: Keith Dawson, Tom Elliott, Jason Kong, Marla Inducil, Eric Norman, Ashkan Vafadaran, Debbie Stevenson,* Reem Al Amoudi,* Terry Broughton,* Laura Hall, Bryan Harrison, Nina Hirvi,* Rossali-Philapil Lee,* Michael Potter. Diabetes Research Group, Winnipeg, Manitoba, Canada: Vincent Woo, Lori Berard, Dixie Hak, Claudia Mandock, Sheri Russell, Teresa Anderlic, Kim Austman, Adrian Bernard, Patty Darvill, Laela Jansen, Tara Klopak, Mathen Mathen, Al-Noor Mawani,* Liam Murphy, Brian Penner, Sherri Pockett, Frank Stockl, Rita Sukkau. Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada: Ehud Ur, Beth Hanway, Glenda McCarthy, Heather Murdock, Tabitha Palmer, Anne Marie Patterson, Melanie Yuille, Carl Abbott, Ali Imran, Alan Cruess, Ann Hoskin-Mott, Tom Ransom, David Shu. Western CCN: University of Washington, Seattle, WA: Jeffery L. Probstfield, Connie Kingry, Ella Mae Kurashige,* Ashley Brown, Marshall A. Corson, Dawn Juliano, Edward Lipkin, Stephanie Moberg, Mark D. Sullivan. Western clinical sites: Northridge Hospital Medical Center, Cardiovascular Center, Northridge, CA: Kevin Ariani, Kanchana Karunaratne, Massoud Azizad, Christopher Chow, Haydee Gutierrez, Jean Partamian, Julie Toven, John Toven. White Memorial Medical Center, Clinical Hypertension Services, Los Angeles, CA: L. Julian Haywood, Vincent DeQuattro,† DePing Li DeQuattro, Luode Wang, Zhi-Ye Song, Lilliana Becerra, Angela Oi Cai, Vikram Kamdar, Cassandra Pruitt. University of Washington Medical Center at Roosevelt, Family Medical Center, Seattle, WA: Allan Ellsworth, Kam Cappocia,* Virginia Hawkins, Nikki Jackson, Diane Britt, Sharon Dobie, Irl Hirsch, Dorrine Khakpour, William Neighbor,* Rex Quaempts. Idaho State University, Department of Family Medicine, Pocatello, ID: Rex Force, Mimi Macdonald, Krysti Pettingill, Barb Hoover,* Cara Liday, Shannon Koester, Tracy Pettinger, Ron Solbrig, Cindy Waldron,* William Woodhouse.* Naval Medical Center San Diego, Cardiology Division, San Diego, CA: Peter E. Linz, Patricia V. Pepper, Marty Engle, Jerry Coopersmith,* Susan Griffin, Rachel Lammers, Julia Leon. Oregon Health & Science University, Section of Diabetes, Portland, OR: Matthew C. Riddle, Kathryn A. Hanavan, Patricia A. McDaniel, Andrew J. Ahmann, Christina Carlson,* Sharlene K. DesRochers, Sarah C. Gammell-Matthews, Diane M. Karl, Elizabeth A. Stephens. Washington State University, Spokane, WA: Carol Wysham, John White,* Debbie Weeks, Linda Kuntsmann, Shannon Yedinak. Kaiser Endocrine Clinic, San Diego, CA: Jim Dudl, Debbie Becker, Laura Lyons, Margaret Murray, Kathleen Harden,* Christina Hawley,* Rachel Stevenson, Patricia Wu. Whittier Institute for Diabetes, Clinical Trials Department, La Jolla,

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CA: George Dailey, Marilyn Baron, Estela Farro, Javiva Horne, Edna Esquer,* Athena Philis-Tsimikas. Minnesota-Iowa CCN: Berman Center for Outcomes & Clinical Research, Minneapolis, MN: Richard H. Grimm, Jr, Brenda B. Kirpach, Marian M. Bartkoske, Colleen M. Boyce, Nicole Druckman,* Arlene M. Gillett,* Julie A. Levin, Gloria J. Livingston, Anne M. Murray, Heather Wood.* HealthPartners Research Foundation, Minneapolis, MN: Karen L. Margolis. Minnesota-Iowa clinical sites: Hennepin ACCORD Clinic, Minneapolis, MN: Kathleen Hall, Sara Kempainen, Joan Kopec, Marcia Madden, Karen L. Margolis, Kim Wood. International Diabetes Center at Park Nicollet, St. Louis Park, MN: Richard Bergenstal, Bradley Davick, Jennifer Hokanson, Mary Johnson, Mamie Lausch, Susan List, Arlen Monk, Rachel Robinson, Karen Smith, Diane Whipple, Greg Damberg, Rachael Hahn, Vickie Koenig, Marilyn Magadan, Sandi Sabin-Smith, Peggy Stewart, Ellie Strock. University of Minnesota, Minneapolis, MN: Elizabeth R. Seaquist, Michael V. Mech, Luke E. Benedict,* Debra J. Demmon, Anjali F. Kumar, Shaina M. Martinson,* Sherry A. Miller, Jyothi P. Rao, J. Bruce Redmon, Joyce E. Swanson,† Julie K. Wimmer. University of Minnesota, Phalen Village Clinic, St. Paul, MN: Kevin Peterson, Lea A. Seaquist, Christy Boese,* Faith Parenteau Ek,* Jamie L. Feldman, Carol J. Lange, Michael V. Mech,* Tai J. Mendenhall,* Andrea M. Peterson, Terri M. Schrock, Daniel P. Spielman,* Sara Velasco,* Joyce C. Weinhandl. Riverside Health Partners Clinic, Department of Endocrinology, Minneapolis, MN: JoAnn Sperl-Hillen, Patrick J. O’Connor, Maureen E. Busch, Becky K. Klein, Theresa Bunkers-Lawson,* Heidi L. Ekstrom,* Heidi S. Gunderson,* Bonnie M. Johnson, John H. MacIndoe,* Donna J. Prewedo, Janet L. Rawl,* Colleen M. Roethke,* Mary Spencer. University of Iowa, Health Care Diabetes Clinical Research and Programs, Iowa City, IA: William I. Sivitz, Sheila M. Wayson, Theresa A. Lower, Lois A. Ahrens, Susan E. Beck, Jaspreet Chahal, Gregory C. Doelle, Victoria M. Guzman, Udaya M. Kabadi, Kurt A. Ochs, Robert G. Spanheimer.* Ohio-Michigan CCN: Case Western Reserve University, Division of Clinical and Molecular Endocrinology, Cleveland, OH: Saul Genuth, Faramarz Ismail-Beigi, Mark Thibonnier,* Laura Vargo,* Carol Kelly,* Theresa Bongorno,* Amanda Dolish,* Laura Pavlik. OhioMichigan clinical sites: University Hospitals of Cleveland, Division of Endocrinology, and University Hospitals Weslake Medical, Cleveland, OH: Faramarz Ismail-Beigi, Leighanne Hustak, Mary Julius, Laura Pavlik, Toni Ross,* William Schwing, Margaret Tiktin, Mary Kay Sullivan,* Louise Strauss,* Kim Behm,* Farideh Eskandari, Cynthia Hall, Debbie Hayes, Karen Horowitz, Souzan Isteitieh, Zuhayr Madhun,* Lynn Richardson, Eileen Seeholzer,* Ajay Sood, Julie Shina. St. Vincent Charity Hospital, Lipid Research Center, Cleveland, OH: Laurie S. Sadler, Mary Griffith,* Ann Hornsby, Karen Klyn, Ellen Ospelt, Lucy Long, Mariellen DeSmit, Peggy McCann, Nicole Pero Schmidt.* University Suburban Health Center, South Euclid, OH: Adrian M. Schnall, Lori Dragmen, Renee Ellert, Jonathan Smith. Cleveland Veterans Affairs (VA) Medical Center (VAMC), Department of Medicine, and Ravenna Community Based Outpatient Clinic, Cleveland, OH: Faramarz Ismail-Beigi, Leighanne Hustak, Mary Julius, William Schwing, Margaret Tiktin, Janet Anselmo,* Farideh Eskandari, Sheila Daymeyer,* Cynthia Hall, Debbie Hayes, Karen Horowitz, Souzan Isteitieh, Cynthia Johnson, Elizabeth Kern, Mary Ann Richmond, Lynn Richardson, Kimberly Roberts,*

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Julie Shina, Ajay Sood, Pam Suhan,* Harris Taylor, Sharon Watts.* The Cleveland Clinic Foundation and Lakewood Hospital Professional Building, Cleveland, OH: Byron J. Hoogwerf, Judith Brakeman, Mary Matzinger, Janet Newsome, Judith Becker,* Susan Bizjack,* Brenda Clingman,* Gloria Depietro,* Renee Ellert,* Carol Horner,* Gisela Bunae, Amir Hamrahian, Augustus Hawkins, Theresa Head, Susan Iannica, Liz Jones, Peter Kaiser, Adi Mehta, Leann Olansky, Amy Orasko, Sethu Reddy, Deb Ross, Lauren Shockley, Elias Siraj,* Melanie Williams, Robert Zimmerman. Your Diabetes Endocrine Nutrition Group, Mentor, OH: Daniel Weiss, Kathleen A. Fagan, Theresa M. Hanslik. Medical University of Ohio, Department of Medicine, Ruppert Health Center, Toledo, OH: Basil Akpunonu, Roberto Franco-Saenz,† Jenny Gilmore, Maureen Gilmore, Lynn Godfrey, Patricia Ross, Becky Bauer, Mellary Chrisstie,* Ann Lopez, Patrick Mulrow, Chris Peters,* Rodica Pop-Busui, Jason Roman,* Crystal Smith.* The Ohio State University Medical Center, Division of Endocrinology, Diabetes and Metabolism, Columbus, OH: Kwame Osei, Elizabeth A. Dziengelewski, Hollie Breedlove, Debra Boland,* Cecilia Casey Boyer, Samuel Cataland, Patricia A. Green, Jocelyn E. Irwin, Dara P. Schuster, Janice L. Varga-Spangler. University of Cincinnati/VA Medical Center, Research Service, Cincinnati, OH: Robert M. Cohen, Kathryn Burton, Jacqueline Craig, Belinda Carter,* Judy Harrer, Robert Hurd,* Dominique Lopez-Stickney, Caroline Pritchard,* Angela Pfefferman,* Barbara A. Ramlo-Halsted,* Catherine McCormick, Cortni Riley, Marsha Strominger. Henry Ford Health System–New Center One, Detroit, MI: Dorothy M. Kahkonen, Terra Cushman, Melissa Roman, Ann M. Stys, Karen White, Mary Austin, Cindy Chatterton, J. Kimberly Francis,* Charlene Jones, Davida Kruger, Amanda McLellan, Fred Whitehouse. Grunberger Diabetes Institute, Bloomfield Hills, MI: George Grunberger, Linda C. Aman, Amtul H. Bandagi, Katherine M. Russell. Northeastern CCN: Columbia University College of Physicians and Surgeons, New York, NY: J. Thomas Bigger, Carlos R. LopezJimenez, Reidar Bornholdt, Linda Busaca, Henry N. Ginsberg, Paul Gonzales, Debbie Gosh,* Pinki Love,† Ana Kosok,* Edriss Robinson,* Richard Steinman, Charmain Watson. Northeastern clinical sites: Jacobi Medical Center, Bronx, NY: Ulrich K. Schubart, Maria Mendoza, Gayotri Goswami, Andres Laufer, Jeanne Russo. Albert Einstein General Clinical Research Center, Bronx, NY: Michael H. Alderman, Lillian Carroll, Mary Jo Sanguily, Janet U. Gorkin, Anna C. Mayer, Lee Ramos, Vanessa Sessoms, Anne Fritts Stewart.* Cornell Internal Medicine Associates, New York, NY: David Brillon, Juan Cordero, Mary Anne Richardson, Esther Wei, Fran Ganz, B. Robert Meyer, Jeff Paley,* Sheila Anderson,* Cassia Charles,* Anne Dwoskin.* The Diabetes Care and Information Center of New York, Flushing, NY: Daniel L. Lorber, Patricia Depree, Azza A. Elmorsy, Jane M. Wendel, Linda L. Zintl, Toni Arenstein,* Phyllis August, Michael Beck, Michael D. Goldberg, Margaret J. Hofacker,* Maria Marotta-Kollarus, Enrico Jose L. Ocampo, Christine A. Resta, Joseph M. Tibaldi. The Cooper Health System, Cherry Hill, NJ: Arnaud Bastien, Susan Grudzinski, Patricia Niblack, Leana Reyes, Tracy Brobyn, Karen Brown,* Monica Casale, Denise Dougherty,* Ghada Haddad, Kathleen Heintz, Mary Kelly,* Dawn Linneman,* Christopher Olivia, Miriam A. Salvador,* Pamela Zee. The Cooper Health System, Pennsville, NJ: Arnaud Bastien, Susan Grudzinski, Patricia Niblack, Leana Reyes, Tracy Brobyn, Karen Brown,*

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The American Journal of Cardiology (www.AJConline.org) Vol 99 (12A) June 18, 2007

Monica Casale, Denise Dougherty,* Ghada Haddad, Kathleen Heintz, Dawn Linneman,* Mary Kelley,* Christopher Olivia, Miriam A. Salvador,* Pamela Zee. Great Lakes Medical Clinic Research, Westfield, NY: Donald F. Brautigam, Rosemary Fischer, June M. Chiarot, Deanna M. Scharf, Barbara Nunn,* Jackie Carlson, Chris Flanders,* Mark R. Hagen. Naomi Berrie Diabetes Center, New York, NY: Robin Goland, Catherine H. Tuck,† Patricia Kringas, Judith Hey-Hadavi,* Jennifer Montes. Ambulatory Care Network at Columbia University, New York, NY: Asqual Getaneh, Jennifer Ramirez, Erida F. Vasquez. Irving Diabetes Research Unit, New York, NY: Daniel S. Donovan, Gerardo Febres, Clara Hernandez,* MaryAnn Jonaitis, Gisette Reyes. State University of New York Downstate Medical Center, Brooklyn, NY: Mary Ann Banerji, Margaret Norton, Priti Patel, Veron Daly, Sondra Hirsch, Cleoffe Jazmin, Ratesh Khillan, Donna Mendonca, Andrea Relingado, Efigenia Sandoval, Mustafa Tiewala. Kings County, Brooklyn, NY: Mary Ann Banerji, Margaret Norton, Priti Patel, Veron Daly, Sondra Hirsch, Cleoffe Jazmin, Ratesh Khillan, Donna Mendonca, Andrea Relingado, Efigenia Sandoval, Mustafa Tiewala. Cooper Clinical Trials Center, The Cooper Health System, Camden, NJ: Arnaud Bastien, Susan Grudzinski, Patricia Niblack, Leana Reyes, Tracy Brobyn, Karen Brown,* Monica Casale, Denise Dougherty,* Ghada Haddad, Kathleen Heintz, Dawn Linneman,* Mary Kelley,* Christopher Olivio, Miriam A. Salvador,* Pamela Zee. Southeastern CCN: Wake Forest University School of Medicine, Department of Public Health Sciences, Winston-Salem, NC: David C. Goff, Jr, John H. Summerson, Caroline S. Blackwell, Alain Bertoni, Rhonda L. Blaine, Julienne K. Kirk, Rhonda L. Spach, Jeff Williamson, Dorothy B. Wishnietsky.* Southeastern clinical sites: Duke University Medical Center, Durham, NC: Mark N. Feinglos, Jennifer Jones, MaryAnn B. Mason, Mary A. Furst, Wanda J. Bean,* Georgianne Gedon-Lipscomb, Jennifer B. Green, Teresa Parham,* Barbara M. Satterwhite,* Connie R. Thacker. Constant Care, Inc., Valdosta, GA: Dhanraj Padhiar, Ray Noel,* Nirmala Padhiar, Shannon West, Annette Francis.* Wake Forest University School of Medicine, Department of Geriatrics/ Gerontology, Winston-Salem, NC: Hal H. Atkinson, Mauro Dibari,* Joli Allen, Judy Stanfield, Thania Delvalle-Fagan, Leslie J. Gordineer, Lindsay Gordon, Michelle Gordon,* Sandra L. Smith, Heather Yates.* Downtown Health Plaza, Winston-Salem, NC: Carolyn F. Pedley, Geraldine Zurek, Miriam Baird, Bettye Dunn, Wendi Kinder,* Sally Mauney. University of North Carolina, Diabetes Care Center, Chapel Hill, NC: John B. Buse, Michelle D. Duclos, Ruth E. Kirby,* Joseph F. Largay, Nicole M. McDermott,* Susan S. Braithwaite, Jean M. Dostou, Elizabeth A. Fasy,* Douglas C. Kelly,* Cristina E. Metz, Daniela Rubin.* Holston Medical Group, Kingsport, TN: Jerry L. Miller, Susan M. Norton, Jamie Weatherly, Sylvia Bishop, Brian Cross, Kim Nuss, Michelle Pratt, Yelena Wood. Carolinas Medical Center Family Practice, Charlotte, NC: Tom Barringer, Cyndi Hoffman, Carol Morris, Pilar Tochiki, Paula Bruner.* Robeson Health Care Corporation, Fairmont Clinic, Fairmont, NC: Robin Peace, Dennis O. Stuart,* Janice Strickland, Lynn Cummings, Dinah Craig, Judy Stanfield.* Robeson Health Care Corporation, Julian T. Pierce Clinic, Pembroke, NC: Robin Peace, Dennis O. Stuart,* Janice Strickland, Lynn Cummings, Dinah Craig, Judy Stanfield.* Wake Forest University School of Medicine, Departments of Internal Medicine and Endocrinology, Winston-Salem, NC: John R. Crouse, Lata Me-

non, Sherry Marion, Donna Davis,* Belice Cabrera,* Jorge Calles, Ted Chandler, Julie Ellis, Ethel Kouba, Emily Myers.* Tulane University Health Science Center, New Orleans, LA: Vivian Fonseca, Roberta Harrison McDuffie, Nana O. AsafuAdjaye, Sharice M. Leger, Patricia Reilly, Gail Afner, Frida Arrey,* Sunil Asnani, Elizabeth Borshard,* Deborah Boyd,* Angelo Cemo, Sunil Chennur,* Patrice Dupart, Rishu Garg,* Gabrielle Porter Girindra,* Biswanath Gouda,* William ItouaN’Ganongo,* Ijeoma Innocent-Ituah,* Christopher Johnson,* Nitesh Kuhadiya, Manisha Kukreja,* Irene Mangan-Mbondi,* Samantha Mason,* Cherie McLain, Jenepher Naylyanya,* Karl Nazereth,* Sharon Nazereth,* Shipra Singh, Tina Thethi, Kendra Varnado,* Ronnie Williams.* Kaiser Permanente, Clinic Atlanta Crescent Medical Center, Tucker, GA: Joshua I. Barzilay, Melanie Eley, Debra Curry-Ball, Stephanie Goodman. VA CCN: Memphis VAMC, Memphis, TN: William C. Cushman, Therese S. Geraci, Sandra M. Walsh, Linda G. Coley, Marshall B. Elam, Diane I. Pickering. VA clinical sites: Memphis VAMC, Hypertension/Lipid Research Clinic, Memphis, TN: Marshall B. Elam, Cathy W. Thompson, Lynne Lichtermann, Sheronda Peeples, Jackie Turner-Bates. Baltimore VAMC, Baltimore, MD: Bruce P. Hamilton, Jennifer Hamilton, Gregory Kuzbida, William Hatten, Jr, Acquanetta Lancaster. Carl T. Hayden VAMC, Phoenix, AZ: James Felicetta, Mary BourneCollo, Mary Ellen Svoboda, Dianne Clothier, Michael Deitz, Carol Flaugher,* Patty Hayward,* Trent Scheibe,* Stephanie Velarde. Atlanta VAMC Medical Service, Decatur, GA: Mary Ellen Sweeney, Debra Harrelson, Susan McConnell, Francoise Watson, Rebecca Johnson, Laurie Whittington. Ralph H. Johnson VAMC, Primary Care, Charleston, SC: Jan Basile, Deborah B. Ham, Bertha North-Lee, Hadi A. Baig, Shakaib U. Rehman. G. V. (Sonny) Montgomery VAMC, Research Department, Jackson, MS: Kent A. Kirchner, Lena Ardell Hinton, Linda Mack, Cathy Adair, Beverly James. VA NY Harbor Healthcare System, New York, NY: Lois Katz, Elizabeth A. Richardson, Andrea G. Goldberg, Amy Nieves, James E. Russo,* Sara A. Sochalski. Washington VAMC, Washington, DC: Vasilios Papademetriou, Barbara Gregory, Rosemarie Alignay, Eric Nylen. St. Louis VAMC, St. Louis, MO: Stephen Giddings, Elizabeth Clark, Arlyn Pittler, Rachel Davis. Central Arkansas Clinic Healthcare System, Little Rock, AR: Debra L. Simmons, Judith Johnson Cooper,* Katherine Dishongh, Raquel Bates,* Krishna Bhaghayath,* Palak Choksi, Shelby Conley,* Steven Elbein, Fred Faas, Zulekha Hamid, Jerrell Johnson, Pippa Johnson, Alice Mayo,* Mary Sha Moriarty, Ganesh Nair,* Dolly Rani, Neda Rasouli, Sufvan Said,* Negah Rassouli, Monica Rodriguez,* Kelly Thomas,* Kimberly Watson, Donna Williams. Other central units: Coordinating Center: Wake Forest University School of Medicine, Winston-Salem, NC: Robert P. Byington, Walter T. Ambrosius, Roger T. Anderson, John Beal, Carolyn Bell, Denise E. Bonds, Sherrard Burton, G. John Chen,* Christy Collins, Delilah Cook, Brenda Craven, Tim Craven, Patty Davis, Debra Dunbar, Gregory W. Evans, Patricia Feeney, Curt D. Furberg, Craig M. Greven, Jason Griffin, John Hepler, Melinda Hire,* Lee Howard, Letitia T. Howard, Nan Hu,* Michael Hough, Wenke Hwang, Sharon Jackson,* Sarah Jaramillo,* Angela Kimel, David Lefkowitz, Annemarie Lopina,* James Lovato, Laura C. Lovato, Michael E. Miller, David Reboussin,* Scott Rushing, Loretta Sanders, Cindy Stowe, Janet Tooze, Michael Walkup,* Sharon Wilmoth, Nancy Woolard. Drug Distribution Center: Albuquerque VAMC, Al-

Ginsberg et al/ACCORD Lipid Trial

buquerque, NM: Dennis Raisch, Robert Ringer, Mike Sather, Brandi DelCurto, Carol Badgett, Eric Preciado, Anna Castillo, Mariann Drago, David Garnand, Sharon S. George, Sharon Jenkins, Jimmy Pontzer, Melissa Van Raden, Frances Torres, Frances Chacon, Amy Yoder, Talaya Martinez, Linda Vasquez, Angela Ward. ECG Reading Center: Wake Forest University School of Medicine, Winston-Salem, NC: Ronald Prineas, Charles Campbell, Lisa Billings, Sharon Hall,* Susan Hensley, Margaret Mills, Zhuming Zhang. Central Chemistry Laboratory: Northwest Lipid Research Laboratories, Seattle, WA: Santica Marcovina, Kathy Gadbois, Michelle Mehan, Marlon Ramirez, Greg Strylewicz, Scott Waddell. ACCORD-MIND MRI Reading Center: University of Pennsylvania, Philadelphia, PA: R. Nick Bryan, Christos Davatzkios, Gul Moonis, Lisa Desiderio, Shannon D’Arcy. Fundus Photograph Reading Center: University of Wisconsin Medical School, Madison, WI: Matthew Davis, Ronald Danis, Samantha Johnson, Nancy Robinson, Larry Hubbard, Barbara Esser, Dennis Thayer, Michael

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Neider. Project Office: National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD: Denise G. Simons-Morton, Lawton Cooper, Michael Domanski, Chuke Nwachuku,* Yves Rosenberg, Marcel Salive,* Peter Savage, Jerome L. Fleg, Jeffrey A. Cutler, Nancy Geller, Dean Follmann,* Michael Proschan,* Cheryl Jennings, Eve Schaeffer,* Peggy Mills,* Jennifer Bittner, Ruth Kirby, Peter Frommer.† National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD: Judith Fradkin, Saul Malozowski, Cathy Myers, Tom Hostetter.* National Institute on Aging (NIA), Bethesda, MD: Lenore Launer, Chau Nguyen. National Eye Institute (NEI), Bethesda, MD: Emily Y. Chew. Centers for Disease Control and Prevention (CDC), Atlanta, GA: K. M. Venkat Narayan, Mike Engelgau, Ping Zhang.

* No longer affiliated with study unit. † Deceased.