[PHNUTR-L] Lowering LDL Chol. Below Recommended Levels in Pts With CHD and DM: The Treating to New Targets (TNT) Study

[Kathrynne Holden, MS, RD]

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http://www.medscape.com/viewarticle/533730

Effect of Lowering LDL Cholesterol Substantially Below Currently 
Recommended Levels in Patients With Coronary Heart Disease and Diabetes: 
The Treating to New Targets (TNT) Study

James Shepherd, MD; Philip Barter, MD, PHD; Rafael Carmena, MD; Prakash 
Deedwania, MD; Jean-Charles Fruchart, PharmD, PHD; Steven Haffner, MD; 
Judith Hsia, MD; Andrei Breazna, PHD; John LaRosa, MD; Scott Grundy, MD, 
PHD; David Waters, MD; for the Treating to New Targets Investigators

Diabetes Care.  2006;29(6):1220-1226.  ©2006 American Diabetes 
Association, Inc.
Posted 06/14/2006
Abstract and Introduction
Abstract

Objective: The Treating to New Targets study showed that intensive 
lipid-lowering therapy with atorvastatin 80 mg/day provides significant 
clinical benefit beyond that afforded by atorvastatin 10 mg/day in 
patients with stable coronary heart disease (CHD). The objective of our 
study was to investigate whether similar benefits of high-dose intensive 
atorvastatin therapy can be achieved in patients with CHD and diabetes.

Research Design and Methods: A total of 1,501 patients with diabetes and 
CHD, with LDL cholesterol levels of <130 mg/dl, were randomized to 
double-blind therapy with either atorvastatin 10 (n = 753) or 80 (n = 
748) mg/day. Patients were followed for a median of 4.9 years. The 
primary end point was the time to first major cardiovascular event, 
defined as death from CHD, nonfatal non–procedure-related myocardial 
infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke.

Results: End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl 
with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A 
primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 
mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg 
(hazard ratio 0.75 [95% CI 0.58–0.97], P = 0.026). Significant 
differences between the groups in favor of atorvastatin 80 mg were also 
observed for time to cerebrovascular event (0.69 [0.48–0.98], P = 0.037) 
and any cardiovascular event (0.85 [0.73–1.00], P = 0.044). There were 
no significant differences between the treatment groups in the rates of 
treatment-related adverse events and persistent elevations in liver enzymes.

Conclusions: Among patients with clinically evident CHD and diabetes, 
intensive therapy with atorvastatin 80 mg significantly reduced the rate 
of major cardiovascular events by 25% compared with atorvastatin 10 mg.


Introduction

Patients with type 2 diabetes are at high risk of coronary heart disease 
(CHD).[1,2] Furthermore, patients with diabetes who experience a 
myocardial infarction have a poorer prognosis and a higher CHD mortality 
rate either immediately or in the long term than nondiabetic patients 
with a prior myocardial infarction.[3,4]

Dyslipidemia is a major contributor to the increased CHD risk in 
patients with type 2 diabetes[5,6] and is characterized by elevated 
levels of triglycerides and low levels of HDL cholesterol. LDL 
cholesterol is similar to that in the general population, although the 
LDL particles are smaller, denser, and more atherogenic. Lowering 
elevated LDL cholesterol levels with statins has demonstrated 
significant reductions in cardiovascular events in patients with 
diabetes and CHD.[7,8,9,10] Due to the high cardiovascular risk 
conferred by type 2 diabetes, current treatment recommendations consider 
patients with diabetes to be CHD risk equivalents[11,12,13] and have 
established an LDL cholesterol goal of <100 mg/dl (2.6 mmol/l) in these 
patients. Recent cardiovascular outcomes trials have raised the issue of 
lower optimal treatment targets for patients with CHD.[14,15] While the 
American Diabetes Association (ADA)-recommended goal of therapy remains 
at an LDL cholesterol <100 mg/dl, the potential for a more aggressive 
LDL cholesterol goal of <70 mg/dl (1.8 mmol/l) has been proposed as a 
treatment option in patients with type 2 diabetes and overt 
cardiovascular disease.[12]

The Treating to New Targets (TNT) study[16] was designed to provide more 
information on the optimal level of LDL cholesterol for cardiovascular 
risk reduction in patients with established CHD. Reduction to a mean LDL 
cholesterol level of 77 mg/dl (2.0 mmol/l) with atorvastatin 80 mg/day 
was associated with a 22% relative risk reduction in cardiovascular 
events compared with reduction to a mean LDL cholesterol of 101 mg/dl 
(2.6 mmol/l) with atorvastatin 10 mg/day.[16] The current subanalysis of 
the TNT study investigates whether similar benefits of lowering lipids 
to levels beyond current recommendations with high-dose intensive statin 
therapy can be achieved in patients with CHD and diabetes.
Research Design and Methods

The design of the TNT study has been described in detail 
previously.[16,17] Patients eligible for inclusion were men and women 
aged 35–75 years with clinically evident CHD, defined as previous 
myocardial infarction, previous or present angina with objective 
evidence of atherosclerotic CHD, or previous coronary revascularization 
procedure. Patients were included in the current analysis if they had 
prior history of diabetes noted on their prescreening form (fasting 
glucose levels at screening were not used). Major exclusion criteria 
included statin hypersensitivity, current liver disease, nephrosis, 
pregnancy or uncontrolled CHD risk factors, CHD event or 
revascularization within less than a month, congestive heart failure, 
unexplained creatine phosphokinase levels more than six times the upper 
limit of normal, life-threatening malignancy, or immunosuppressive or 
lipid-lowering drug treatment.

Any previously prescribed lipid-regulating drugs were discontinued at 
screening, and all patients required a wash-out period of 1–8 weeks (8 
weeks for those who had and 1 week for those who had not previously 
received lipid-regulating drugs). To ensure that all patients at 
baseline achieved LDL cholesterol levels consistent with the current 
guidelines for the treatment of stable CHD, patients with LDL 
cholesterol between 130 and 250 mg/dl (3.4–6.5 mmol/l) and triglycerides 
≤600 mg/dl (6.8 mmol/l) entered an 8-week open-label period with 
atorvastatin 10 mg/day. At the end of the run-in phase (week 0), those 
patients with a mean LDL cholesterol <130 mg/dl (3.4 mmol/l) (determined 
at weeks –4 and –2) were randomized to double-blind therapy with either 
atorvastatin 10 or 80 mg/day. During the double-blind period, follow-up 
visits occurred at week 12 and at months 6, 9, and 12 in the 1st year 
and every 6 months thereafter. At each visit, vital signs, clinical end 
points, adverse events, and concurrent medication information were 
collected. In addition, on alternating visits (i.e., annually), physical 
examinations and electrocardiograms were performed and laboratory 
specimens collected.
Efficacy Outcome Measures

The primary efficacy outcome measure was the time to first occurrence of 
a major cardiovascular event, defined as CHD death, nonfatal 
non–procedure-related myocardial infarction, resuscitated cardiac 
arrest, and fatal or nonfatal stroke. Secondary efficacy outcome 
measures included any cardiovascular event, major coronary event (CHD 
death, nonfatal non–procedure-related myocardial infarction, or 
resuscitated cardiac arrest), any coronary event, cerebrovascular event, 
peripheral arterial disease, documented angina, hospitalization for 
congestive heart failure, and all-cause mortality.
Statistical Analysis

Cholesterol inclusion/exclusion criteria were selected to achieve an 
average level of 100 mg/dl (2.6 mmol/l) in the atorvastatin 10 mg/day 
treatment arm. To reach an average LDL cholesterol level in the 
comparator group of ~75 mg/dl (1.9 mmol/l), atorvastatin 80 mg/day was 
chosen. Differences between the atorvastatin 80- and 10-mg treatment 
groups were based on log-rank analyses of the first occurrence of a 
major cardiovascular event during the 5-year follow-up period in each 
group. Relative risks and hazard ratios (HRs) and their 95% CIs were 
calculated using the Cox regression model. Two-sided P values <0.05 were 
regarded as significant. Tests for heterogeneity were used to determine 
whether the treatment effects observed in patients with diabetes 
differed from those in patients without diabetes.
Results

Of a total of 10,001 patients randomized, 1,501 (15%) had diabetes, of 
whom 753 received atorvastatin 10 mg and 748 received atorvastatin 80 
mg. Patients with diabetes were generally slightly older (63 vs. 61 
years), more overweight (BMI 30.4 vs. 28.5 kg/m2), and included more 
women (27 vs. 19%) than the overall population. Hypertension (71 vs. 
54%), coronary bypass (55 vs. 47%), peripheral arterial disease (21 vs. 
12%), and cerebrovascular accident (9 vs. 5%) were more prevalent in the 
diabetes subgroup than in the overall population. Baseline 
characteristics of patients with diabetes were similar between the two 
treatment groups, as were baseline LDL cholesterol, total cholesterol, 
triglycerides, HDL cholesterol, and apolipoprotein B. The proportion of 
patients managing their diabetes with oral hypoglycemic agents, insulin, 
or a combination thereof was similar between treatment groups ( Table 1 ).
Changes in Lipids

During the open-label period, atorvastatin 10 mg reduced LDL cholesterol 
from a mean of 160.3 mg/dl (4.1 mmol/l) to 96.2 mg/dl (2.5 mmol/l) for 
all patients with diabetes. End-of-treatment LDL cholesterol levels 
increased by 3% to a mean of 98.6 mg/dl (2.5 mmol/l) in patients with 
diabetes who continued atorvastatin 10 mg, while a further reduction of 
19% to a mean of 77.0 mg/dl (2.0 mmol/l) was observed in patients with 
diabetes who were assigned to atorvastatin 80 mg (P < 0.0001). Similar 
treatment effects were observed for total cholesterol and triglycerides. 
At the end of treatment, total cholesterol increased from baseline by 2% 
to a mean of 177.9 mg/dl (4.6 mmol/l) with atorvastatin 10 mg and was 
further reduced by 13% to a mean of 150.6 mg/dl (3.9 mmol/l) with 
atorvastatin 80 mg. Triglycerides increased from baseline by 11% to 
178.3 mg/dl (2.0 mmol/l) with atorvastatin 10 mg, while atorvastatin 80 
mg resulted in an additional reduction of 10% to 145.3 mg/dl (1.6 
mmol/l). There was little change in HDL cholesterol in either treatment 
group over the course of the study.
Efficacy Outcomes

Over the 5 years of double-blind treatment, a primary event was 
experienced by 103 patients with diabetes (13.8%) receiving atorvastatin 
80 mg and 135 patients (17.9%) receiving atorvastatin 10 mg. This 
represented a 25% reduction in the risk of major cardiovascular events 
in favor of the high-dose group (HR 0.75 [95% CI 0.58–0.97], P = 0.026) 
(Fig. 1). Consistent with the significant findings in the overall 
population, trends toward a benefit in favor of atorvastatin 80 mg were 
observed for the time to the primary end point components nonfatal 
non–procedure-related myocardial infarction (0.79 [0.55–1.14], P = 
0.202), fatal/nonfatal stroke (0.67 [0.43–1.04], P = 0.075), and CHD 
death (0.74 [0.47–1.18], P = 0.203), although there were insufficient 
events in the subgroup of patients with diabetes to reach significance. 
Significant differences between the groups in favor of atorvastatin 80 
mg were observed for the secondary outcomes of time to cerebrovascular 
event (0.69 [0.48–0.98], P = 0.037) and time to cardiovascular event 
(0.85 [0.73–1.00], P = 0.044; Fig. 2). Consistent with the overall 
population, there was no significant difference between the treatments 
for all-cause mortality (Fig. 2). There was a reduction in 
cardiovascular mortality with atorvastatin 80 mg (5.2%) compared with 
atorvastatin 10 mg (6.5%), while noncardiovascular mortality was higher 
in the atorvastatin 80-mg group (5.6%) than in the atorvastatin 10-mg 
group (3.3%). However, the study was not powered to detect a significant 
difference between the treatment groups for mortality.

     Figure 1.

     Kaplan-Meier estimates of the incidence of major cardiovascular 
events in patients with diabetes. *Composite of CHD death, nonfatal 
non–procedure-related myocardial infarction, resuscitated cardiac 
arrest, and fatal or nonfatal stroke.



     Figure 2.

     HRs and heterogeneity tests for primary and secondary outcomes in 
patients with and without diabetes. Composite end points include major 
cardiovascular events (CHD death, nonfatal non–procedure-related 
myocardial infarction, resuscitated cardiac arrest, and fatal or 
nonfatal stroke), any cardiovascular event (cerebrovascular event, 
congestive heart failure [CHF]with hospitalization, CHD death, 
myocardial infarction, resuscitated cardiac arrest, coronary 
revascularization, and documented angina), major coronary events (CHD 
death, nonfatal non–procedure-related myocardial infarction, and 
resuscitated cardiac arrest), any coronary event (major coronary event, 
coronary revascularization, procedure-related myocardial infarction, and 
documented angina), and cerebrovascular events (fatal and nonfatal 
stroke and transient ischemic attack).



For all primary and secondary efficacy outcomes, there was a higher 
incidence of events in the subgroup of patients with diabetes than in 
the overall group, and there was no significant heterogeneity of 
treatment effect between patients with and without diabetes (Fig. 2). A 
decreased incidence of primary event rates was observed in the 
atorvastatin 80- compared with the 10-mg group across all quintiles of 
patient age and duration of diabetes and in patients with HbA1c (A1C) 
≤7% and A1C >7% ( Table 2 ).

Additional benefit from atorvastatin 80 vs. 10 mg was observed early in 
the disease process of diabetes, with patients across all quintiles of 
diabetes duration in the atorvastatin 80-mg group experiencing a reduced 
incidence of first stroke compared with those in the atorvastatin 10-mg 
group. Moreover, patients with and without good glycemic control 
randomized to atorvastatin 80 mg experienced a lower incidence of first 
major cardiovascular event, coronary event, stroke, nonfatal 
non–procedure-related myocardial infarction, and CHD death than patients 
randomized to atorvastatin 10 mg, with a significant reduction in risk 
for major cardiovascular events in patients with A1C ≤7%.
Safety and Tolerability

In the diabetic population, treatment-related adverse events were 
experienced by 41 patients (5.4%) receiving atorvastatin 10 mg and 52 
patients (7.0%) receiving atorvastatin 80 mg. These rates are similar to 
those observed in the overall TNT population (5.8% for atorvastatin 10 
mg and 8.1% for atorvastatin 80 mg). Treatment-related myalgia was 
reported in 27 patients (3.6%) receiving atorvastatin 10 mg and 18 
patients (2.4%) receiving atorvastatin 80 mg. Persistent elevations more 
than three times the upper limit of normal (occurring twice within 4–10 
days) in alanine aminotransferase and/or aspartate aminotransferase were 
observed in three patients (0.4%) receiving atorvastatin 10 mg and seven 
patients (0.9%) receiving atorvastatin 80 mg. There were no significant 
differences between the treatment groups in the rate of 
treatment-related adverse events, including myalgia, or persistent 
elevations in liver enzymes. No incidents of rhabdomyolysis were 
reported in either treatment group with diabetes.

Of 8,500 patients without diabetes at screening, 865 (10.2%) developed 
diabetes during the course of the study, 425 in the atorvastatin 10-mg 
group and 440 in the atorvastatin 80-mg group (odds ratio 1.04, P = 0.59).
Conclusions

The TNT study confirmed and extended the growing body of evidence 
indicating that lowering LDL cholesterol to values well below currently 
recommended levels with more intensive statin therapy is associated with 
additional cardiovascular benefit.[14-16,18,19] The current subanalysis 
of the TNT study indicates that these benefits are consistent in 
patients with diabetes and CHD. Among patients with clinically evident 
CHD and diabetes, intensive therapy with atorvastatin 80 mg 
significantly reduced the rate of major cardiovascular events by 25% 
compared with a more moderate regimen of atorvastatin 10 mg (P = 0.026).

For secondary outcomes, intensive therapy with atorvastatin 80 mg 
significantly reduced the rate of all cardiovascular events and 
cerebrovascular events compared with atorvastatin 10 mg. For major 
coronary events, all coronary events, congestive heart failure with 
hospitalization, peripheral arterial disease, and all-cause mortality, 
HRs and CIs were consistent with the overall study population, and there 
was no significant heterogeneity of treatment effect between patients 
with and without diabetes, indicating that the significant results of 
the main study hold true for patients with diabetes.

An increased event rate was observed for the subgroup of patients with 
diabetes compared with the overall TNT study group across all primary 
and secondary efficacy outcomes, providing a clear indication of the 
extremely high cardiovascular risk of these patients with CHD and 
diabetes. That said, the statin treatment effect did not differ 
significantly across other cardiovascular risk factors, such as 
increasing patient age, screening LDL cholesterol, duration of diabetes, 
and A1C. Event rates in the diabetic patients in both the atorvastatin 
10- and 80-mg arms of the TNT study were lower than those observed in 
diabetic patients in the treatment arms of other statin secondary 
prevention trials,[7,8,9,10] and the lower event rate observed across 
the full range of age, diabetes duration, and glycemic control in the 
high-dose atorvastatin group further demonstrates that patients with CHD 
and diabetes receive benefit from intensive versus more moderate statin 
treatment.

Data from this TNT subanalysis demonstrated that lowering LDL 
cholesterol with intensive atorvastatin therapy to levels <100 mg/dl 
(2.6 mmol/l) presents no additional safety concerns in patients with 
diabetes compared with the overall population or compared with more 
moderate lowering of LDL cholesterol with atorvastatin 10 mg. Despite no 
significant difference between the treatment groups for mortality, the 
rate was low in both treatment arms. Of further note in this population 
at significant risk of cardiovascular death, the atorvastatin 80-mg arm 
is the first cohort from secondary prevention studies[14,20,21] for 
which the incidence of cardiovascular deaths did not exceed 
noncardiovascular deaths.

This is a subanalysis of patients with diabetes in TNT and thus a post 
hoc analysis. The potential cardiovascular benefits observed are 
consistent with trends in previous studies in patients with diabetes and 
CHD.[7,8,9] Furthermore, the prospective design of the TNT study in 
reducing LDL cholesterol from a baseline mean of <130 mg/dl (3.4 
mmol/l), following earlier treatment with atorvastatin 10 mg, to either 
a target of 100 mg/dl (2.6 mmol/l) or 75 mg/dl (1.9 mmol/l), allows some 
insight into the benefits of lowering beyond current recommended targets 
in patients with diabetes and CHD.

In 2005, the ADA updated its clinical practice recommendations for 
patients with diabetes and cardiovascular disease, noting that these 
individuals are at very high risk for subsequent clinical events.[12] On 
the basis of randomized trials of moderate versus intensive lipid 
lowering in very-high-risk (albeit nondiabetic) populations,[15,19] the 
ADA advised that use of high-dose statin to achieve an LDL cholesterol 
level of <70 mg/dl was a therapeutic option in diabetic patients with 
cardiovascular disease. The analysis of patients with diabetes in the 
TNT study strengthens the evidence for this recommendation by 1) 
confirming the high cardiovascular event rate in CHD patients who also 
have diabetes, 2) providing direct evidence of cardiovascular risk 
reduction with high-dose statin therapy in this population, and 3) 
demonstrating that this risk reduction is independent of baseline LDL 
cholesterol. Pending a definitive trial, these data suggest that the use 
of high-dose statin to achieve an LDL cholesterol level considerably 
<100 mg/dl[12] may be appropriate for patients with diabetes and CHD, 
irrespective of their initial LDL cholesterol level, age, duration of 
diabetes, or glycemic control.

Table 1. Baseline Characteristics of Patients with Diabetes


     Baseline characteristic (at randomization)	Atorvastatin 10 mg 
Atorvastatin 80 mg
     n	753	748
     Men	544 (72.2)	550 (73.5)
     Age (years)	62.8 ± 8.0	63.2 ± 7.9
     Race
       White	670 (89.0)	670 (89.6)
       Black	48 (6.4)	39 (5.2)
       Other	35 (4.6)	39 (5.2)
     Systolic blood pressure (mmHg)	134.7 ± 17.3	134.3 ± 17.6
     Diastolic blood pressure (mmHg)	76.8 ± 9.5	77.1 ± 9.9
     BMI (kg/m2)	30.7 ± 5.6	30.1 ± 5.0
     Diabetes duration (years)	8.3 ± 8.5	8.8 ± 8.8
     Diabetes control
       Oral hypoglycemic drug only	324 (43.0)	326 (43.6)
       Insulin only	101 (13.4)	94 (12.6)
       Insulin + oral hypoglycemic drug	157 (20.8)	146 (19.5)
       No diabetes medications*	171 (22.7)	182 (24.3)
       Fasting plasma glucose (mg/dl)	153.9 ± 49.3	154.0 ± 49.9
       Plasma creatinine (mg/dl)	1.19 ± 0.23	1.19 ± 0.25
       A1C (%)	7.4 ± 1.3	7.4 ± 1.2
     Cardiovascular history
       Angina	606 (80.5)	632 (84.5)
       Hypertension	536 (71.2)	525 (70.2)
       Former smoker	484 (64.3)	446 (59.6)
       Myocardial infarction	414 (55.0)	442 (59.1)
       Coronary artery bypass graft	420 (55.8)	403 (53.9)
       Coronary angioplasty	370 (49.1)	402 (53.7)
       Peripheral arterial disease	151 (20.1)	168 (22.5)
       Congestive heart failure	105 (13.9)	108 (14.4)
       Current smoker	72 (9.6)	86 (11.5)
       Cerebrovascular accident	67 (8.9)	68 (9.1)
     Lipids
       LDL cholesterol
         mg/dl	96.7 ± 17.8	95.6 ± 18.4
         mmol/l	2.50 ± 0.46	2.47 ± 0.48
       Total cholesterol
         mg/dl	174.9 ± 24.5	174.7 ± 24.6
         mmol/l	4.52 ± 0.63	4.52 ± 0.64
       Triglycerides
         mg/dl	169.2 ± 78.9	171.3 ± 80.9
         mmol/l	1.91 ± 0.89	1.93 ± 0.91
       HDL cholesterol
         mg/dl	44.6 ± 9.2	45.2 ± 11.1
         mmol/l	1.15 ± 0.24	1.17 ± 0.29
       Apolipoprotein B	113.6 ± 20.0	112.5 ± 19.5

     Data are means ± SD or n (%).
     *Patients who were not recorded as taking oral hypoglycemic agents 
or insulin at study entry.


Table 2. Major Cardiovascular Event Rate in Patients With Diabetes by 
A1C, age, Screening LDL Cholesterol, and Duration of Diabetes


      	Atorvastatin 10 mg (n = 753)	Atorvastatin 80 mg (n = 748)	P value 
for heterogeneity
     Event rate (%)	n	Event rate (%)	n
     A1C ≤7	16.2	290	9.2	261	
     A1C >7	20.6	359	15.9	359	0.30
     Quintiles of baseline age (years)
       ≤52.9	16.3	147	9.0	155	
       >52.9–59.1	11.6	146	11.2	142	
       >59.1–64.5	20.4	167	17.2	134	
       >64.5–69.4	19.0	158	14.8	142	
       >69.4	22.2	135	17.0	165	0.24
     Quintiles of screening LDL cholesterol (mg/dl)
       ≤142	17.9	134	11.9	143	
       >142–154	18.5	151	13.0	154	
       >154–166	16.9	160	13.2	144	
       >166–184	21.4	154	14.6	157	
       >184	15.1	152	16.0	150	0.78
     Quintiles of duration of diabetes (years)
       ≤2	15.0	147	12.3	138	
       >2–4	19.3	109	13.8	116	
       >4–8	15.8	184	12.3	162	
       >8–14	18.5	130	13.3	150	
       >14	24.2	161	15.4	162	0.99
       A1C ≤7	16.2	290	9.2	261	
       A1C >7	20.6	359	15.9	359	0.30




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Acknowledgements

Study participants are listed in the TNT core article.[16] We also 
acknowledge contributions made by Holly Schachner, Sheila Auster, Liz 
Cusenza, Miriam Marshood (employees of Pfizer), and Steve Dobson in the 
development of this article.
Funding Information

Funding for this study was provided by Pfizer.

The costs of publication of this article were defrayed in part by the 
payment of page charges. This article must therefore be hereby marked 
"advertisement" in accordance with 18 U.S.C. Section 1734 solely to 
indicate this fact.
Disclaimer

A table elsewhere in this issue shows conventional and Système 
International (SI) units and conversion factors for many substances.
Abbreviation Notes

ADA = American Diabetes Association; CHD = coronary heart disease; TNT = 
Treating to New Targets
Reprint Address

James Shepherd, Biochemistry, Royal Infirmary, Glasgow, G4 OSF, U.K. 
E-mail: jshepherd at gri-biochem.org.uk

James Shepherd, MD,1 Philip Barter, MD, PHD,2 Rafael Carmena, MD,3 
Prakash Deedwania, MD,4 Jean-Charles Fruchart, PHARMD, PHD,5 Steven 
Haffner, MD,6 Judith Hsia, MD,7 Andrei Breazna, PHD,8 John LaRosa, MD,9 
Scott Grundy, MD, PHD,10 David Waters, MD,11 for the Treating to New 
Targets Investigators

1 Department of Vascular Biochemistry, University of Glasgow, Glasgow, U.K.
2 The Heart Research Institute, Department of Medicine, University of 
Sydney, Sydney, Australia
3 Endocrinology Department, Clinic University Hospital, University of 
Valencia, Valencia, Spain
4 Cardiology Division, Veterans Affairs Central California Health Care, 
University of California San Francisco School of Medicine, San 
Francisco, California
5 Lipoprotein and Atherosclerosis Research Unit, Institut National de la 
Santé et de la Recherche Médicale, Pasteur Institute, Lille, France
6 Department of Medicine, University of Texas Health Science Center, San 
Antonio, Texas
7 Division of Cardiology, George Washington University Medical Center, 
Washington, DC
8 Biometrics Department, Pfizer, New York, New York
9 State University of New York Downstate Medical Center, State 
University of New York Health Science Center, Brooklyn, New York
10 Center for Human Nutrition, Departments of Clinical Nutrition and 
Internal Medicine, University of Texas Southwestern Medical Center, 
Dallas, Texas
11 Division of Cardiology, School of Medicine, San Francisco General 
Hospital, University of California San Francisco School of Medicine, San 
Francisco, California
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