Action to Control Cardiovascular Risk in Diabetes

Action to Control Cardiovascular Risk in Diabetes
Title	Action to Control Cardiovascular Risk in Diabetes
Acronym	ACCORD
Year	2008–2014
Study type	Randomized controlled trial
Location	United States, Canada, Puerto Rico
Principal investigators	Johns Hopkins University, Brigham and Women's Hospital, National Heart, Lung, and Blood Institute
Participants	10,251 adults with type 2 diabetes
Interventions	Intensive glucose lowering, blood pressure control, lipid therapy
Outcomes	Major cardiovascular events, mortality

Action to Control Cardiovascular Risk in Diabetes is a large multicenter randomized controlled trial that investigated strategies to reduce cardiovascular events among adults with type 2 diabetes mellitus by targeting glycemic, blood pressure, and lipid risk factors. The trial was funded by the National Institutes of Health through the National Heart, Lung, and Blood Institute and conducted at centers affiliated with institutions such as Johns Hopkins University and Brigham and Women's Hospital. ACCORD's outcomes informed clinical practice, guideline committees, and regulatory agencies including the Food and Drug Administration and the European Medicines Agency.

Background and Rationale

The trial addressed the high cardiovascular morbidity and mortality observed in populations such as patients treated at Mayo Clinic and cohorts followed by the Framingham Heart Study, and responded to evidence from landmark studies including the United Kingdom Prospective Diabetes Study, DCCT/EDIC, and UKPDS showing microvascular benefits of intensive glycemic control but uncertain macrovascular effects. Investigators from centers including Massachusetts General Hospital and University of Toronto designed ACCORD to test whether more aggressive risk-factor modification would reduce events like myocardial infarction and stroke recorded in registries such as the AHA statistics and cohorts like the Nurses' Health Study.

Study Design and Methods

ACCORD used a factorial randomized design with parallel arms modeled on precedent trials such as ALLHAT and HOPE. The glycemia trial randomized participants to intensive versus standard glycated hemoglobin targets, borrowing statistical planning methods used by trials at Vanderbilt University and data coordinating practices akin to those at the Clinical and Translational Science Awards program. Sub-trials included a blood pressure component comparing intensive versus standard systolic targets, and a lipid component that evaluated combination therapy similar to trials run at Cleveland Clinic and Mayo Clinic. Endpoints were adjudicated by committees similar to those used in SPRINT and PROVE IT-TIMI 22.

Participants and Interventions

ACCORD enrolled 10,251 adults with established type 2 diabetes mellitus at high cardiovascular risk from clinical sites including Stanford University, University of Pittsburgh Medical Center, and international affiliates in Canada and Puerto Rico. Inclusion criteria mirrored risk profiles observed in cohorts like the Framingham Heart Study with prior cardiovascular disease or multiple risk factors. The intensive glycemia arm targeted glycated hemoglobin <6.0% using algorithms and medications available from manufacturers and clinics affiliated with institutions like Harvard Medical School; the standard arm targeted 7.0–7.9% consistent with prior consensus statements by organizations such as the American Diabetes Association and the European Association for the Study of Diabetes. The blood pressure trial targeted systolic <120 mmHg versus <140 mmHg using agents including ACE inhibitors and diuretics commonly studied at centers like University College London and Imperial College London; the lipid trial randomized participants to fenofibrate added to simvastatin versus simvastatin alone, paralleling therapies evaluated in trials associated with University of Oxford and University of Edinburgh.

Outcomes and Results

The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death, adjudicated similarly to endpoints in TIMI and CHARM trials. The glycemia intensive strategy did not reduce the primary composite and was associated with an unexpected increase in all-cause mortality, prompting early cessation of the intensive glycemia arm. The blood pressure arm did not show a significant reduction in the primary composite, though it achieved lower stroke rates consistent with findings in PROGRESS. The lipid arm showed no significant primary benefit for the composite endpoint but suggested subgroup effects analogous to those reported in secondary analyses of HPS. Results were widely disseminated at meetings of organizations such as the American Heart Association, European Society of Cardiology, and reported in major journals following precedent set by publications from The New England Journal of Medicine and The Lancet.

Safety and Adverse Events

Intensive glycemic control was associated with higher rates of severe hypoglycemia and weight gain, adverse events comparable to signals noted in trials conducted at centers like Columbia University and University of California, San Francisco. The rise in mortality prompted detailed safety reviews by data and safety monitoring boards similar to those convened in trials at Johns Hopkins University and consultations with regulatory agencies including the Food and Drug Administration. The blood pressure and lipid interventions produced adverse event profiles consistent with known effects of antihypertensive and fibrate therapies observed in multicenter trials such as ALLHAT and FIELD.

Interpretation and Clinical Implications

ACCORD demonstrated that intensive lowering of glycated hemoglobin to near-normal levels in high-risk, long-duration type 2 diabetes mellitus patients did not reduce major cardiovascular events and increased mortality, leading to reassessment of aggressive HbA1c targets in guidelines from organizations like the American Diabetes Association and the European Association for the Study of Diabetes. The findings emphasized individualized targets for patients similar to recommendations from panels at Mayo Clinic and Cleveland Clinic and reinforced the importance of comprehensive risk management highlighted by programs at institutions such as Johns Hopkins University.

Legacy and Influence on Guidelines

ACCORD influenced major guideline updates by the American Diabetes Association, European Society of Cardiology, and National Institute for Health and Care Excellence, and informed subsequent trials including ADVANCE, VADT, and cardiovascular outcomes trials of newer agents evaluated at centers like Mount Sinai Hospital and Vanderbilt University Medical Center. Its data contributed to regulatory discussions at the Food and Drug Administration and to shifts in practice at hospitals including Massachusetts General Hospital and Brigham and Women's Hospital, reinforcing patient-centered, risk-stratified approaches to glycemic and cardiovascular risk management. Category:Clinical trials in diabetes