Series: Landmark Trials in Endocrinology & Metabolism | Study #23
Category: Type 2 Diabetes · Glycaemic Control | Design: Multicentre, double-blind, randomised controlled trial | n: 10,251 | Follow-up: 3.5 years (stopped early)
📋 Summary
Authors: Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group
Journal: N Engl J Med 2008;358:2545–2559 | DOI: 10.1056/NEJMoa0802743
The ACCORD glycaemia trial enrolled 10,251 patients with type 2 diabetes mellitus (mean age 62.2 years, median HbA1c 8.1%) who had either established cardiovascular disease or at least two cardiovascular risk factors. Participants were randomised to intensive glycaemic therapy targeting an HbA1c below 6.0% or standard therapy targeting an HbA1c of 7.0 to 7.9%. At one year, stable median HbA1c levels of 6.4% and 7.5% were achieved in the intensive and standard groups respectively. The primary composite outcome was nonfatal MI, nonfatal stroke, or cardiovascular death. After a mean follow-up of 3.5 years, the trial was stopped early because of excess mortality in the intensive-therapy group. The primary outcome occurred in 352 patients in the intensive-therapy group and 371 in the standard-therapy group (HR 0.90; 95% CI 0.78 to 1.04; p=0.16), a non-significant difference. However, 257 patients in the intensive-therapy group died compared with 203 in the standard-therapy group (HR 1.22; 95% CI 1.01 to 1.46; p=0.04), a statistically significant 22% excess mortality. Hypoglycaemia requiring assistance occurred in 10.5% of patients in the intensive group versus 3.5% in the standard group (p<0.001). Weight gain above 10 kg was more frequent in the intensive group (27.8% vs 14.1%; p<0.001).
📊 Key Findings
| Outcome | Intensive | Standard | Effect Size |
|---|---|---|---|
| Primary MACE (MI, stroke, CV death) | 352 events | 371 events | HR 0.90 (0.78–1.04) · p=0.16 · NS |
| All-cause mortality | 257 deaths | 203 deaths | HR 1.22 (1.01–1.46) · p=0.04 — HARM |
| HbA1c achieved | 6.4% | 7.5% | Difference −1.1% |
| Severe hypoglycaemia requiring assistance | 10.5% | 3.5% | p<0.001 · 3-fold increase |
| Weight gain >10 kg | 27.8% | 14.1% | p<0.001 |
💬 Expert Commentary
ACCORD is one of the most discussed and debated trials in the modern history of diabetes medicine, and its premature termination due to excess mortality in the intensive glycaemic treatment group was genuinely unexpected. The epidemiological relationship between HbA1c and cardiovascular risk, which had been used to support the hypothesis that intensive glucose lowering would reduce cardiovascular events, was well established, and no prior randomised trial had identified a mortality hazard from tighter glycaemic control. The ACCORD mortality signal was therefore alarming. The cause of the excess deaths in the intensive group was not definitively identified. Analyses suggested that hypoglycaemia, particularly severe hypoglycaemia, may have contributed, but the mortality excess was not fully explained by hypoglycaemic events and appeared to be distributed across the intensive treatment arm in a pattern not clearly linked to any single adverse event type. The rapidity of HbA1c reduction and the high medication burden in the intensive group, including complex multi-drug regimens that included thiazolidinediones (rosiglitazone) in a large proportion of participants, have been identified as possible contributors.
ACCORD is best read together with ADVANCE (Study #24) and VADT (Study #25), the other two large glycaemia trials published in the same year. ADVANCE, which targeted HbA1c below 6.5% using a gliclazide-based regimen in a partially different population, found microvascular but not macrovascular benefit and did not observe a mortality hazard. VADT found neither benefit nor harm. The three trials collectively established that intensive glucose lowering in high-risk patients with long-standing type 2 diabetes does not produce cardiovascular benefit and may cause harm in some subgroups, shifting the consensus away from aggressive HbA1c targeting in older patients with established CVD or long diabetes duration. The implications of ACCORD were reflected in guideline revisions that recommended HbA1c targets be individualised based on age, disease duration, hypoglycaemia risk, and cardiovascular comorbidity rather than uniformly targeting below 7.0% in all patients.
Limitations: The trial was stopped early, limiting interpretation of the full intended duration. The cause of excess mortality in the intensive arm was not definitively established. Rosiglitazone use was prevalent in the intensive arm, and later cardiovascular safety concerns about rosiglitazone have raised questions about its contribution to the mortality signal. The study was funded by NIH.
🔑 BOTTOM LINE
ACCORD demonstrated that targeting an HbA1c below 6.0% in high-risk patients with type 2 diabetes and established cardiovascular disease increased all-cause mortality by 22% without significantly reducing cardiovascular events, establishing that very intensive glycaemic targets are harmful in this population and fundamentally reshaping guidelines to promote individualised HbA1c targets based on patient risk.
⭐ Clinical Impact Rating: ●●●●● Practice-defining (critical negative trial)
