Action to Control Cardiovascular Risk in Diabetes (ACCORD)

BACKGROUND:

Currently, about 17 million Americans have been diagnosed with diabetes and more than 90
percent of them have type 2 diabetes. The number of people with this form of diabetes,
formerly known as adult onset or non-insulin dependent diabetes, is growing rapidly. By
2050, the number of Americans with diagnosed diabetes is projected to increase by 165
percent to 29 million, of whom 27 million will have the type 2 form. Cardiovascular disease
(CVD) is the leading cause of death in people with type 2 diabetes; these individuals die of
CVD at rates two to four times higher than those who do not have diabetes. They also
experience more nonfatal heart attacks and strokes.

Type 2 diabetes is associated with older age and is more common in those who are overweight
or obese and have a family history of diabetes. Women with a history of diabetes during
pregnancy, adults with impaired glucose tolerance, people with a sedentary lifestyle, and
members of a minority race/ethnicity are also at a greater risk for developing type 2
diabetes. African Americans, Hispanic/Latino Americans, American Indians, and some Asian
Americans and Pacific Islanders are at particularly high risk for type 2 diabetes.

DESIGN NARRATIVE:

The three strategies tested in ACCORD included the following: (1) Blood sugar - ACCORD was
designed to determine whether lowering blood glucose to a level closer to normal than called
for in current guidelines reduces CVD risk. The study estimated effects on CVD of that level
compared with a level that is usually targeted. (2) Blood pressure - many people with type 2
diabetes have high blood pressure. The blood pressure part of the trial was designed to
determine the effects of lowering blood pressure in the context of good blood sugar control,
that is to determine whether lowering blood pressure to normal (systolic pressure less than
120 mm Hg) will better reduce CVD risk, as compared to a usually-targeted level in current
clinical practice (i.e., below the definition of hypertension; systolic pressure less than
140 mm Hg). (3) Blood Fats - Many people with diabetes have high levels of LDL ("bad")
cholesterol and triglycerides, as well as low levels of HDL ("good") cholesterol. ACCORD
participants who are selected for this part of the trial were assigned to an intervention to
improve blood fat levels. This part of the study looked at the effects of lowering LDL
cholesterol and blood triglycerides and increasing HDL cholesterol compared to an
intervention that only lowers LDL cholesterol, all in the context of good blood sugar
control. A drug from a class of drugs called "fibrates" was used to lower triglycerides and
increase HDL cholesterol, whereas a drug from the class of drugs called "statins" was used
to lower LDL cholesterol.

All ACCORD participants received blood sugar treatment from the study. Based on the second
trial (Blood Pressure or Lipid) they were assigned to, participants also received their high
blood pressure or cholesterol care from the study. Study participants received all
medication and treatments related to the study free of charge. Individuals who selected for
and consented to participate in the ACCORD study continued to see their personal physician
for all other health care.

In summary, the ACCORD Study was a double 2x2 factorial design with factors consisting of:
intensive versus standard glycemic control, intensive versus standard blood pressure
control, and blinded fenofibrate or placebo in combination with simvastatin to maintain
desirable LDL-C levels. All 10,251 participants were randomized to the glycemic
interventions; a subgroup of 4,733 participants who met the blood pressure entry criteria
were randomized to the blood pressure interventions in one 2x2 trial; and a distinct
subgroup of 5,518 participants who met the lipid entry criteria were randomized to the lipid
interventions in the second 2x2 trial. All participants had established type 2 diabetes and
were recruited from 77 clinical centers in the United States (64 sites) and Canada (13
sites).

On February 6, 2008, the National Heart, Lung and Blood Institute (NHLBI) announced that
participants in the intensive glycemia treatment would be transitioned to the ACCORD
standard glycemic treatment approach due to higher mortality in the intensive treatment
group terminating the experimental arm of the Glycemia Trial early. The Blood Pressure and
Lipid trials continued as designed to their planned termination in 2009.

Inclusion Criteria:

- Diagnosed with type 2 diabetes mellitus, as determined by the new American Diabetes
Association guidelines, which include a fasting plasma glucose level greater than 126
mg/dl (7.0 mmol/l), or a 2-hour postload value in the oral glucose tolerance test of
greater than 200 mg/dl, with confirmation by a retest

- For participants aged 40 years or older, history of CVD (heart attack, stroke,
history of coronary revascularization, history of peripheral or carotid
revascularization, or demonstrated angina)

- For participants aged 55 years or older, a history of CVD is not required, but
participant must be considered to be at high risk for experiencing a CVD event due to
existing CVD, subclinical disease, or 2+ CVD risk factors

- HbA1c 7.5%-9% (if on more drugs) or 7.5%-11% (if on fewer drugs)