Action to Control Cardiovascular Risk in Diabetes (ACCORD)

Overview

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.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Factorial Assignment
    • Primary Purpose: Prevention
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 2009

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 2×2 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 2×2 trial; and a distinct subgroup of 5,518 participants who met the lipid entry criteria were randomized to the lipid interventions in the second 2×2 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.

Interventions

  • Drug: Anti-hyperglycemic Agents
    • 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%).
  • Drug: Anti-hypertensive Agents
    • Multiple anti-hypertensive agents as needed to reach Blood Pressure Trial arm-specific goals (intensive control <120 mm Hg; standard control <140 mm Hg).
  • Drug: Blinded fenofibrate or placebo plus simvastatin
    • 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.

Arms, Groups and Cohorts

  • Experimental: Glycemia Trial: intensive control
    • 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%.
  • Active Comparator: Glycemia Trial: standard control
    • 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%.
  • Experimental: BP Trial: intensive control
    • Open label administration of anti-hypertensive agents to reduce and maintain systolic blood pressure (SBP) level to <120 mmHg.
  • Active Comparator: BP Trial: standard control
    • Open label administration of multiple anti-hypertensive agents to maintain SBP level <140 mm Hg.
  • Experimental: Lipid Trial: fenofibrate
    • 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.
  • Placebo Comparator: Lipid Trial: placebo
    • 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.

Clinical Trial Outcome Measures

Primary Measures

  • 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 Frame: 4.9 years
    • 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.
  • First Occurrence of Major Cardiovascular Event (MCE) in the Blood Pressure Trial.
    • Time Frame: 4.7 years
    • Time to first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Primary outcome for Blood Pressure Trial.
  • First Occurrence of Major Cardiovascular Event (MCE) in the Lipid Trial.
    • Time Frame: 4.7 years
    • Time to first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death in Lipid Trial participants.

Secondary Measures

  • Death From Any Cause in the Glycemia Trial.
    • Time Frame: 4.9 years
    • 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).
  • Stroke in the Blood Pressure Trial.
    • Time Frame: 4.7 years
    • Time to first occurrence of nonfatal or fatal stroke among participants in the BP Trial.
  • First Occurrence of MCE or Revascularization or Hospitalization for Congestive Heart Failure (CHF) in Lipid Trial.
    • Time Frame: 4.7 years
    • Time to first occurrence of nonfatal myocardial infarction, nonfatal stroke, cardiovascular death, revascularization procedure or hospitalization for CHF in Lipid Trial participants.

Participating in This Clinical Trial

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)

Gender Eligibility: All

Minimum Age: 40 Years

Maximum Age: 79 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • National Heart, Lung, and Blood Institute (NHLBI)
  • Collaborator
    • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Denise Simons-Morton, MD, PhD, Study Director, National Heart, Lung, and Blood Institute (NHLBI)
    • William Friedewald, MD, Study Chair, Columbia University, New York, NY
    • Robert Byington, PhD, Principal Investigator, Wake Forest University, Winston-Salem, NC

References

Cushman WC, Grimm RH Jr, Cutler JA, Evans GW, Capes S, Corson MA, Sadler LS, Alderman MH, Peterson K, Bertoni A, Basile JN; ACCORD Study Group. Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007 Jun 18;99(12A):44i-55i. Epub 2007 Apr 16.

Williamson JD, Miller ME, Bryan RN, Lazar RM, Coker LH, Johnson J, Cukierman T, Horowitz KR, Murray A, Launer LJ; ACCORD Study Group. The Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Study (ACCORD-MIND): rationale, design, and methods. Am J Cardiol. 2007 Jun 18;99(12A):112i-122i. Epub 2007 Apr 12.

Sullivan MD, Anderson RT, Aron D, Atkinson HH, Bastien A, Chen GJ, Feeney P, Gafni A, Hwang W, Katz LA, Narayan KM, Nwachuku C, O'Connor PJ, Zhang P; ACCORD Study Group. Health-related quality of life and cost-effectiveness components of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: rationale and design. Am J Cardiol. 2007 Jun 18;99(12A):90i-102i. Epub 2007 Apr 13.

Bonds DE, Kurashige EM, Bergenstal R, Brillon D, Domanski M, Felicetta JV, Fonseca VA, Hall K, Hramiak I, Miller ME, Osei K, Simons-Morton DG; ACCORD Study Group. Severe hypoglycemia monitoring and risk management procedures in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007 Jun 18;99(12A):80i-89i. Epub 2007 Apr 17.

Kingry C, Bastien A, Booth G, Geraci TS, Kirpach BR, Lovato LC, Margolis KL, Rosenberg Y, Sperl-Hillen JM, Vargo L, Williamson JD, Probstfield JL; ACCORD Study Group. Recruitment strategies in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007 Jun 18;99(12A):68i-79i. Epub 2007 Apr 12.

Ginsberg HN, Bonds DE, Lovato LC, Crouse JR, Elam MB, Linz PE, O'connor PJ, Leiter LA, Weiss D, Lipkin E, Fleg JL; ACCORD Study Group. Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007 Jun 18;99(12A):56i-67i. Epub 2007 Apr 12.

Goff DC Jr, Gerstein HC, Ginsberg HN, Cushman WC, Margolis KL, Byington RP, Buse JB, Genuth S, Probstfield JL, Simons-Morton DG; ACCORD Study Group. Prevention of cardiovascular disease in persons with type 2 diabetes mellitus: current knowledge and rationale for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007 Jun 18;99(12A):4i-20i. Epub 2007 Apr 12. Review.

Gerstein HC, Riddle MC, Kendall DM, Cohen RM, Goland R, Feinglos MN, Kirk JK, Hamilton BP, Ismail-Beigi F, Feeney P; ACCORD Study Group. Glycemia treatment strategies in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007 Jun 18;99(12A):34i-43i. Epub 2007 Apr 19.

ACCORD Study Group, Buse JB, Bigger JT, Byington RP, Cooper LS, Cushman WC, Friedewald WT, Genuth S, Gerstein HC, Ginsberg HN, Goff DC Jr, Grimm RH Jr, Margolis KL, Probstfield JL, Simons-Morton DG, Sullivan MD. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol. 2007 Jun 18;99(12A):21i-33i. Epub 2007 Apr 16.

Chew EY, Ambrosius WT, Howard LT, Greven CM, Johnson S, Danis RP, Davis MD, Genuth S, Domanski M; ACCORD Study Group. Rationale, design, and methods of the Action to Control Cardiovascular Risk in Diabetes Eye Study (ACCORD-EYE). Am J Cardiol. 2007 Jun 18;99(12A):103i-111i. Epub 2007 Apr 13.

Citations Reporting on Results

Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59. doi: 10.1056/NEJMoa0802743. Epub 2008 Jun 6.

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