Endocrinology · 2008
ACCORD
Action to Control Cardiovascular Risk in Diabetes
For decades after the DCCT established tight glycemic control as the standard for type 1 diabetes, a widespread assumption in diabetology held that the same principle should apply to type 2 disease. The UKPDS in 1998 showed modest cardiovascular benefit from early intensive control in newly diagnosed patients, and guidelines progressively pushed HbA1c targets lower. By the mid-2000s, many specialists recommended targets below 7% or even below 6.5% in patients with established cardiovascular disease, the group presumed to have the most to gain.
ACCORD was designed to test that assumption directly. The trial assigned 10,251 adults with type 2 diabetes and either established cardiovascular disease or multiple risk factors to an intensive glucose control arm targeting HbA1c below 6%, or to a standard arm targeting 7 to 7.9%. Hertzel Gerstein co-led the glycemia component. The multicenter ACCORD Study Group enrolled patients across North America, with a median baseline HbA1c of approximately 8.1% and median diabetes duration of around ten years.
The intensive arm was halted in February 2008, after a median of 3.5 years of follow-up, when the Data Safety Monitoring Board identified that all-cause mortality was higher in the intensively treated group, with a hazard ratio of 1.22. Cardiovascular death accounted for most of the excess. The announcement came at a time when both ADVANCE (published the same month) and VADT (published later in 2008) were also reporting results, and together the three trials reframed the glycemia question for high-risk patients.
The mechanism behind the mortality signal was never definitively established. Severe hypoglycemia occurred more frequently in the intensive arm, and hypoglycemia-driven arrhythmia was a proposed explanation, but analyses trying to link hypoglycemic events directly to mortality were inconclusive. Other investigators pointed to the rapid rate of HbA1c lowering in the intensive arm, the use of combination pharmacotherapy with multiple agents simultaneously, or possible detrimental effects of specific drugs. No single mechanism was confirmed.
ACCORD did not negate tight control broadly. It specifically demonstrated harm in a population of high-risk, longer-duration patients pushed to near-normal glycemia through intensive pharmacotherapy. Combined with ADVANCE and VADT, it shifted guidelines toward individualized targets and away from a single HbA1c goal for all patients with type 2 diabetes. Current guidelines from the ADA and other bodies explicitly recommend loosening targets in older patients, those with long disease duration, established cardiovascular disease, or history of severe hypoglycemia, a framework that ACCORD's results made necessary.
Key People
- Hertzel Gerstein — Co-principal investigator; led the glycemia arm
- ACCORD Study Group — Multicenter North American investigator consortium
- William Cushman — Co-investigator; led the blood pressure arm of ACCORD
- Henry Ginsberg — Co-investigator; led the lipid arm of ACCORD
N Engl J Med. 2008
Related landmarks
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