Action to Control Cardiovascular Risk in Diabetes (ACCORD) "ACCORD"

Completed

Phase 3 Results

Trial Description

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

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.

Conditions

Interventions

  • Hypoglycemic Agents, Intensive BP treatment. Fenofibrate + simvastatin, Standard glycemia control, Standard BP control, Drug
  • Hypoglycemic Agents Drug
    Intervention Desc: Multiple drugs including insulins and oral hypoglycemia agents for HbA1c less than 6%
    ARM 1: Kind: Experimental
    Label: 1: Intensive glycemia control
    Description: A strategy of intensive glycemia treatment to HbA1 less than 6%
  • Intensive BP treatment Drug
    Intervention Desc: A strategy of multiple BP agents to reduce SBP less than 120 mm Hg
    ARM 1: Kind: Experimental
    Label: 3: Intensive BP control
    Description: A strategy of BP treatment for SBP less than 120 mm Hg
  • Fenofibrate + simvastatin Drug
    Intervention Desc: Blinded fenofibrate or placebo + simvastatin 20-40 mg/d
    ARM 1: Kind: Experimental
    Label: 5: Fibrate
    Description: Blinded fenofibrate + simvastatin 20-40 mg/d
  • Standard glycemia control Drug
    Intervention Desc: A strategy of glycemia drugs for HbA1c 7%-7.9%
    ARM 1: Kind: Experimental
    Label: 2: Standard glycemia control
    Description: A strategy of multiple drugs to treat HbA1c to 7.0%-7.9%
  • Standard BP control Drug
    Other Names: Enalapril-folic acid,amlodipine,hydrochlorothiazide
    Intervention Desc: A strategy of BP drugs for SBP less than 140 mm Hg
    ARM 1: Kind: Experimental
    Label: 4: Standard BP control
    Description: A strategy of BP treatment for SBP less than 140 mm Hg
  • Anti-hyperglycemic Agents Drug
    Other Names: glimepiride (Amaryl); metformin (Glucophage); repaglinide (Gluconorm, Prandin); rosiglitazone (Avandia); pioglitazone (Actos); human regular insulin (Novolin ge Toronto); human NPH (Novolin N); human mixed (Novolin 70/30); human isophane (Novolin ge NPH);
    Intervention Desc: 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%).
    ARM 1: Kind: Experimental
    Label: Glycemia Trial: intensive control
    Description: 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%.
    ARM 2: Kind: Experimental
    Label: Glycemia Trial: standard control
    Description: 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%.
  • Anti-hypertensive Agents Drug
    Other Names: benazepril (Lotensin, Zestril, Altace); chlorthalidone (Thalitone); metoprolol (Toprol XL); diltiazem (Tiazac); plendil (Felodipine); terazosin (Hytrin); candesartan (Atacand); valsartan (Diovan); furosemide; reserpine; hydralazine; carvedilol (Coreg); tr
    Intervention Desc: Multiple anti-hypertensive agents as needed to reach Blood Pressure Trial arm-specific goals (intensive control <120 mm Hg; standard control <140 mm Hg).
    ARM 1: Kind: Experimental
    Label: BP Trial: intensive control
    Description: Open label administration of anti-hypertensive agents to reduce and maintain systolic blood pressure (SBP) level to <120 mmHg.
    ARM 2: Kind: Experimental
    Label: BP Trial: standard control
    Description: Open label administration of multiple anti-hypertensive agents to maintain SBP level <140 mm Hg.
  • Blinded fenofibrate or placebo plus simvastatin Drug
    Other Names: fenofibrate (Tricor)
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Lipid Trial: fenofibrate
    Description: 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.
    ARM 2: Kind: Experimental
    Label: Lipid Trial: placebo
    Description: 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.

Trial Design

  • Allocation: Randomized
  • Masking: Open Label
  • Purpose: Prevention
  • Endpoint: Efficacy Study
  • Intervention: Factorial Assignment

Patient Involvement

Patients will be randomly assigned to either a standard or aggressive control of blood sugar, then based on their blood pressure and cholesterol levels, assigned to one of the other two groups.

Outcomes

Type Measure Time Frame Safety Issue
Primary Lowered risk of CVD in each of the 3 medical treatment strategies: lowered blood sugar, lowered blood pressure (&lt;120mmHg systolic), blood fats (lower LDL and increase HDL).
Secondary Total mortality.
Primary First occurence of a major CVD event, specifically nonfatal heart attack, nonfatal stroke, or cardiovascular death (measured throughout the study) 5-1/2 years Yes
Secondary total mortality 5-1/2 years Yes
Primary 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. 4.9 years Yes
Primary First Occurrence of Major Cardiovascular Event (MCE) in the Blood Pressure Trial. 4.7 years Yes
Primary First Occurrence of Major Cardiovascular Event (MCE) in the Lipid Trial. 4.7 years Yes
Secondary Death From Any Cause in the Glycemia Trial. 4.9 years Yes
Secondary Stroke in the Blood Pressure Trial. 4.7 years Yes
Secondary First Occurrence of MCE or Revascularization or Hospitalization for Congestive Heart Failure (CHF) in Lipid Trial. 4.7 years Yes

Sponsors