Action to Control Cardiovascular Risk in Diabetes (ACCORD)

Study Overview
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Brief Summary
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The purpose of this study is to prevent major cardiovascular events (heart attack, stroke, or cardiovascular death) in adults with type 2 diabetes mellitus using intensive glycemic control, intensive blood pressure control, and multiple lipid management.

Detailed Description
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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.

Official Title
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Action to Control Cardiovascular Risk in Diabetes (ACCORD)

Conditions
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Atherosclerosis, Cardiovascular Diseases, Hypercholesterolemia, Hypertension, Diabetes Mellitus, Type 2, Diabetes Mellitus, Coronary Disease

Intervention / Treatment
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* Drug: Anti-hyperglycemic Agents
* Drug: Anti-hypertensive Agents
* Drug: Blinded fenofibrate or placebo plus simvastatin


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glycemia Trial: intensive control<br>Open label administration of oral anti-hyperglycemic agents and/or insulin in combination with dietary/lifestyle advice as needed to achieve glycated hemoglobin (HbA1c) levels <6.0%. | Drug: Anti-hyperglycemic Agents<br>* Multiple drugs including insulins and oral anti-hyperglycemic agents as needed to reach Glycemia Trial arm-specific goals (intensive control <6%; standard control 7.0-7.9%).<br>* Other names: Acarbose;|
| Active Comparator: Glycemia Trial: standard control<br>Open label administration of oral anti-hyperglycemic agents and/or insulin in combination with dietary/lifestyle advice as needed to achieve glycated hemoglobin (HbA1c) levels of 7.0 - 7.9%. | Drug: Anti-hyperglycemic Agents<br>* Multiple drugs including insulins and oral anti-hyperglycemic agents as needed to reach Glycemia Trial arm-specific goals (intensive control <6%; standard control 7.0-7.9%).<br>* Other names: Acarbose;|
| Experimental: BP Trial: intensive control<br>Open label administration of anti-hypertensive agents to reduce and maintain systolic blood pressure (SBP) level to <120 mmHg. | Drug: Anti-hypertensive Agents<br>* Multiple anti-hypertensive agents as needed to reach Blood Pressure Trial arm-specific goals (intensive control <120 mm Hg; standard control <140 mm Hg).<br>* Other names: amlodipine / benazepril (Lotrel);|
| Active Comparator: BP Trial: standard control<br>Open label administration of multiple anti-hypertensive agents to maintain SBP level <140 mm Hg. | Drug: Anti-hypertensive Agents<br>* Multiple anti-hypertensive agents as needed to reach Blood Pressure Trial arm-specific goals (intensive control <120 mm Hg; standard control <140 mm Hg).<br>* Other names: amlodipine / benazepril (Lotrel);|
| Experimental: Lipid Trial: fenofibrate<br>Double blind administration of 160 mg/day of fenofibrate in participants with estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m2 or 54 mg/day in patients with eGFR <50 mL/min/1.73m2 in combination with open label simvastatin. | Drug: Blinded fenofibrate or placebo plus simvastatin<br>* Double blind administration of 160 mg/day of fenofibrate in participants with estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m2 or 54 mg/day in patients with eGFR <50 mL/min/1.73m2 or matching placebo in combination with open label simvastatin 20 - 40 mg/day.<br>* Other names: fenofibrate (Tricor);|
| Placebo Comparator: Lipid Trial: placebo<br>Double blind administration of placebo matching either 160 mg/day in participants with eGFR ≥50 mL/min/1.73m2 or 54 mg/day in participants with eGFR <50 mL/min/1.73m2 in combination with open label simvastatin. | Drug: Blinded fenofibrate or placebo plus simvastatin<br>* Double blind administration of 160 mg/day of fenofibrate in participants with estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m2 or 54 mg/day in patients with eGFR <50 mL/min/1.73m2 or matching placebo in combination with open label simvastatin 20 - 40 mg/day.<br>* Other names: fenofibrate (Tricor);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First Occurrence of a Major Cardiovascular Event (MCE); Specifically Nonfatal Heart Attack, Nonfatal Stroke, or Cardiovascular Death (Measured Throughout the Study) in the Glycemia Trial. | Time to first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. This was the primary outcome measure in all three trials: Glycemia (all participants), Blood Pressure (subgroup of participants not in Lipid Trial), and Lipid (subgroup of participants not in Blood Pressure Trial). In the Glycemia Trial, a finding of higher mortality in the intensive arm group led to an early discontinuation of therapy after a mean of 3.5 years of follow-up. Intensive arm participants were transitioned to standard arm strategy over a period of 0.2 year and followed for an additional 1.2 years to the planned end of the Glycemia Trial while participating in one of the other sub-trials (BP or Lipid) to their planned completion. | 4.9 years | 
| First Occurrence of Major Cardiovascular Event (MCE) in the Blood Pressure Trial. | Time to first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Primary outcome for Blood Pressure Trial. | 4.7 years | 
| First Occurrence of Major Cardiovascular Event (MCE) in the Lipid Trial. | Time to first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death in Lipid Trial participants. | 4.7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death From Any Cause in the Glycemia Trial. | Time to death from any cause. Secondary measure for Glycemia Trial. A finding of higher mortality in the intensive-therapy group led to an early discontinuation of therapy after a mean of 3.5 years of follow-up. Intensive arm participants were transitioned to standard arm strategy over a period of 0.2 year and followed for an additional 1.2 years to the planned end of the Glycemia Trial while participating in one of the other sub-trials (BP or Lipid). | 4.9 years | 
| Stroke in the Blood Pressure Trial. | Time to first occurrence of nonfatal or fatal stroke among participants in the BP Trial. | 4.7 years | 
| First Occurrence of MCE or Revascularization or Hospitalization for Congestive Heart Failure (CHF) in Lipid Trial. | Time to first occurrence of nonfatal myocardial infarction, nonfatal stroke, cardiovascular death, revascularization procedure or hospitalization for CHF in Lipid Trial participants. | 4.7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Non-Insulin-Dependent