New England Journal Medicine: The of

new england
Effects of Combination Lipid

journal
ofmedicine
Therapy in Type
2 Diabetes
The
established in 1812
april 29, 2010

Mellitus
vol. 362
no. 17
The ACCORD Study Group*
A bs tr act
Background
We investigated whether combination therapy with a statin plus a

fibrate, as compared with statin monotherapy, would reduce the
risk of cardiovascular disease in patients with type 2 diabetes
mellitus who were at high risk for cardiovascular disease.
majority
of
high-risk
patients with type 2
diabetes.
(ClinicalTrials.gov number,
NCT00000620.)
Methods
We randomly assigned 5518 patients with type 2 diabetes who

were being treated with open-label simvastatin to receive either
masked fenofibrate or placebo. The primary outcome was the first
occurrence of nonfatal myocardial infarction, nonfatal stroke, or
death from cardiovascular causes. The mean follow-up was 4.7
years.
Results
The annual rate of the primary outcome was 2.2% in the

fenofibrate group and 2.4% in the placebo group (hazard ratio in
the fenofibrate group, 0.92; 95% confi- dence interval [CI], 0.79 to
1.08; P=0.32). There were also no significant differences between
the two study groups with respect to any secondary outcome. Annual
rates of death were 1.5% in the fenofibrate group and 1.6% in the
placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P= 0.33).
Prespecified subgroup analyses suggested heterogeneity in
treatment effect according to sex, with a benefit for men and possible harm for women (P= 0.01 for interaction), and a possible
interaction according to lipid subgroup, with a possible benefit for
patients with both a high baseline triglyceride level and a low
baseline level of high-density lipoprotein cholesterol (P= 0.057 for
interaction).
Conclusions
The combination of fenofibrate and simvastatin did not reduce the

rate of fatal cardiovascular events, nonfatal myocardial infarction,
or nonfatal stroke, as compared with simvastatin alone. These
results do not support the routine use of combination therapy with
fenofibrate and simvastatin to reduce cardiovascular risk in the
The New England Journal of Medicine
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Copyright 2010 Massachusetts Medical Society. All rights reserved.
The members of the Writing Committee (Henry N. Ginsberg, M.D., Marshall B. Elam,
M.D., Laura C. Lovato, M.S., John
R. Crouse III, M.D., Lawrence A. Leiter, M.D., Peter Linz, M.D., William T. Friede- wald,
M.D., John B. Buse, M.D., Ph.D., Hertzel C. Gerstein, M.D., Jeffrey Probst- field, M.D.,
Richard H. Grimm, M.D., Ph.D., Faramarz Ismail-Beigi, M.D., Ph.D., J. Thomas Bigger,
M.D., David C. Goff, Jr., M.D., Ph.D., William C. Cush- man, M.D., Denise G. SimonsMorton, M.D., Ph.D., and Robert P. Byington, Ph.D.) assume responsibility for the integrity of the article. Address reprint re- quests to Dr. Ginsberg at the Department of
Medicine, Columbia University Col- lege of Physicians and Surgeons, Rm. PH 10-305,
New York, NY 10032, or at hng1@ columbia.edu.
.org. The affiliations of members

of the Writing Committee are
listed in the Ap- pendix.
This
article
(10.1056/NEJMoa1001282)
was
published on March 14, 2010, and
updated on March 18, 2010, at
NEJM.org.
N Engl J Med 2010;362:1563-74.
Copyright 2010 Massachusetts Medical Society.
*The members of the Action to Control Cardiovascular Risk in Diabetes(ACCORD) Study

Group are listed in Section 20 in Supplementary Appendix 1, available with the full
text of this article at NEJM
n engl j med 362;17
nejm.org april 29, 2010
The New England Journal of Medicine

Downloaded from nejm.org on October 27, 2016. For personal use only. No other uses without permission.
Copyright 2010 Massachusetts Medical Society. All rights reserved.
1563
T he
ne w engl and jour nal
atients with type 2 diabetes

mellitus have an increased incidence
of athero- sclerotic cardiovascular
disease.1-4 This in- crease is
attributable, in part, to associated risk
factors, including hypertension and
dyslipidemia. The latter is characterized
by elevated plasma triglyceride levels,
low levels of high-density lipoprotein
(HDL) cholesterol, and small, dense lowden- sity lipoprotein (LDL) particles.5,6
The Action to Control Cardiovascular
Risk in Diabetes (ACCORD) study was
designed to test the effect of intensive
treatment of blood glucose and either
blood pres- sure or plasma lipids on
cardiovascular outcomes in 10,251
patients with type 2 diabetes who were
at high risk for cardiovascular disease.
Here we present the findings of the
ACCORD lipid trial
(ACCORD Lipid).
Although statins are efficacious in
patients with type 2 diabetes, rates of
cardiovascular events remain elevated in
such
patients
even
after
statin
7-9
treatment.
Fibrate therapy in patients
with type 2 diabetes reduced the rate of
coronary heart disease events in the
Veterans Affairs HDL Interven- tion Trial
(VA-HIT;
ClinicalTrials.gov
number,
10
NCT00035711)
but not in the
Fenofibrate In- tervention and Event
Lowering in Diabetes (FIELD) trial
(Current Controlled Trials number,
ISRCTN64783481).11 However, a post hoc
analysis of data from the FIELD study
suggested a benefit for patients with
both elevated triglyceride levels and
low HDL cholesterol levels.12 Previous
fibrate
studies
in
subjects
with
10,11
diabetes
or
in
those
without
diabetes13-15 did not address the role of
such drugs in patients receiving statin
therapy. The hypothesis that we tested
in ACCORD Lipid was that in high-risk
patients
with
type
2
diabetes,
combination treatment with a fibrate (both
to raise HDL cholesterol levels and to
lower triglyceride levels) and a statin
(to reduce LDL cholesterol levels) would
reduce the rate of cardiovascular events,
as compared with treatment with a
statin alone.
of
m edicine
Methods
Study Design
The rationale and designs

for the various components of ACCORD have
been reported previously.16-20 The ACCORD study
was a randomized trial
conducted at 77 clinical
sites organized into seven networks in the United
States and Canada. (For
a full list of participating institutions and investigators, see Section 20 in Supplementary Appendix 1, available with the full text of this article at
NEJM.org.) The trial was sponsored by the Na- tional
Heart, Lung, and Blood Institute (NHLBI), and the
protocol was approved by a review panel at the
NHLBI, as well as by the institutional review board
or ethics committee at each center.
In the ACCORD study, all patients were randomly assigned to receive either intensive glycemic
control (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a glycated
hemoglobin level of 7.0 to 7.9%). The results of this
comparison have been reported previously.20 A
subgroup of patients in the ACCORD study were also
enrolled in the ACCORD Lipid trial and un- derwent
randomization, in a 2-by-2 factorial design, to
receive simvastatin plus either fenofibrate or placebo.
Randomization occurred between Jan- uary 11, 2001,
and October 29, 2005. End-of-study visits were
scheduled between March and June 2009.
Additional details regarding the trial protocol and
amendments are provided in Supple- mentary
Appendix 2, also available with the full text of this
article at NEJM.org.
Eligibility
more. If patients had evidence of

clinical cardiovascular disease, the
age range was limited to 40 to 79
years; if they had evidence of
subclinical cardiovascular disease or at
least two additional cardiovascular risk
factors, the age range was compressed to 55 to 79 years. Patients
were specifi- cally eligible to participate
in the lipid trial if they also had the
following: an LDL cholesterol level of
60 to 180 mg per deciliter (1.55 to 4.65
mmol per liter), an HDL cholesterol
level below 55 mg per deciliter (1.42
mmol per liter) for women and blacks
or below 50 mg per deciliter (1.29
mmol per liter) for all other groups, and
a triglyceride level below 750 mg per
deciliter (8.5 mmol per liter) if they
were not receiving lipid therapy or below 400 mg per deciliter (4.5 mmol per
liter) if they were receiving lipid therapy.
All patients provided written informed
consent. Additional details regarding
eligibility and the protocol for the enrollment of patients are available in
Section 3 in Supplementary Appendix 1.
All patients in the ACCORD study had type 2 diabetes and a glycated hemoglobin level of 7.5% or
1564
n engl j med 362;17
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april 29, 2010
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new england

Effects of Combination Lipid

april 29, 2010

The ACCORD Study Group*

We investigated whether combination therapy with a statin plus a

We randomly assigned 5518 patients with type 2 diabetes who

The annual rate of the primary outcome was 2.2% in the

The combination of fenofibrate and simvastatin did not reduce the

.org. The affiliations of members

*The members of the Action to Control Cardiovascular Risk in Diabetes(ACCORD) Study

n engl j med 362;17

nejm.org april 29, 2010

The New England Journal of Medicine

ne w engl and jour nal

atients with type 2 diabetes

The rationale and designs

more. If patients had evidence of

n engl j med 362;17

april 29, 2010

Thank you for using www.freepdfconvert.com service!

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