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Evevident
Original paper
2008NEJMEndocrinology/Metabolism

ACCORD

Effects of intensive glucose lowering in type 2 diabetes

RCTType 2 diabetes

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Overview

In high-risk T2DM, targeting near-normal A1c increased mortality and did not reduce major CV events enough to justify the strategy.

Clinical takeaway

ACCORD is the cautionary counterweight to aggressive A1c targets: intensive glucose lowering is not automatically better in older/high-risk patients with established cardiovascular risk.

Key result

The intensive arm was stopped early for higher all-cause mortality (HR 1.22; 95% CI 1.01-1.46).

Practice impact

Individualize A1c goals; avoid reflexively pushing older/high-risk patients to near-normal A1c.

Evidence

Study design

Randomized controlled trial (glycemia arm).

Enrollment

10,251

Follow-up

Intensive glycemia stopped early at mean 3.5 years; total follow-up ~5 years.

Geography

United States, Canada

Clinical question

Does intensive glycemic control reduce major cardiovascular events in high-risk type 2 diabetes?

Population

  • Patients with T2DM and cardiovascular disease or high cardiovascular risk.

Intervention

Intensive therapy targeting A1c <6.0%.

Comparator

Standard therapy targeting A1c 7.0-7.9%.

Primary outcome

Composite of nonfatal MI, nonfatal stroke, or CV death.

Intensive glucose lowering did not significantly reduce the primary composite cardiovascular outcome and was associated with higher all-cause mortality.

Hazard ratio / 0.9 / CI 95% CI 0.78-1.04 / p=0.16

Key results

  • Primary composite outcome: 6.9% with intensive vs 7.2% with standard therapy; HR 0.90; 95% CI 0.78-1.04; p=0.16 (not significant).
  • All-cause mortality was higher with intensive therapy: HR 1.22; 95% CI 1.01-1.46; p=0.04, prompting early termination of the intensive arm at a mean of 3.5 years.
  • Nonfatal MI was reduced with intensive therapy (HR 0.76), but cardiovascular death was increased (HR 1.35).
  • Severe hypoglycemia requiring assistance and weight gain >10 kg were more common with intensive therapy.

Harms

  • All-cause mortality was higher with intensive glucose lowering (HR 1.22; 95% CI 1.01-1.46).
  • Severe hypoglycemia requiring assistance was more common with intensive therapy.
  • Weight gain of more than 10 kg was more common with intensive therapy.

Clinical Use

When to cite

  • When discussing why intensive glycemic targets can be harmful in high-risk patients with longstanding type 2 diabetes.

Practice impact

  • Individualize A1c goals; avoid reflexively pushing older/high-risk patients to near-normal A1c.

Applicability

  • Most applicable to older patients with long-standing T2DM and established cardiovascular disease or high cardiovascular risk.
  • Does not apply to younger, newly diagnosed patients, in whom tighter control has microvascular benefit.

Limitations

  • Mechanism of increased mortality remains debated.
  • Population was high-risk and not newly diagnosed.
  • Rapid A1c lowering and complex multi-drug regimens may have contributed to harm.

Common misinterpretations

  • Do not generalize ACCORD to all diabetes; tight control still reduces microvascular disease in younger, newly diagnosed patients.
  • The harm signal was tied to the intensive glycemic strategy, not to any single glucose-lowering drug.

Related evidence

UKPDS - Context

Citation

Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559. doi:10.1056/NEJMoa0802743

As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events.