What are the implications of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial on HbA1c (Hemoglobin A1c) targets for patients with type 2 diabetes?

ACCORD Trial: Implications for HbA1c Targets in Type 2 Diabetes

Key Finding: Intensive Glycemic Control Below 6.5% Increases Mortality Risk

The ACCORD trial demonstrated that targeting HbA1c below 6.0% in patients with established type 2 diabetes and cardiovascular disease or multiple risk factors resulted in a 22% increase in all-cause mortality and a 35% increase in cardiovascular death, leading to early trial termination. 1

Critical Trial Details

The ACCORD trial enrolled 10,251 middle-aged and older participants (mean age 62.2 years) with established type 2 diabetes (median baseline HbA1c 8.1%) and either existing cardiovascular disease or multiple cardiovascular risk factors. 1, 2

Treatment arms:

• Intensive group: Target HbA1c <6.0%, achieved 6.4% 1
• Standard group: Target HbA1c 7.0-7.9%, achieved 7.5% 1

The trial was stopped early at mean follow-up of 3.5 years due to safety concerns. 1

Mortality and Cardiovascular Outcomes

Primary harms identified:

• All-cause mortality increased by 22% (HR 1.22,95% CI 1.01-1.46) 1
• Cardiovascular death increased by 35% (HR 1.35,95% CI 1.04-1.76) 1
• Severe hypoglycemia requiring assistance increased 3-fold 1
• Weight gain >10 kg occurred in 27.8% vs 14.1% in standard group 1
• Increased fluid retention 1

Cardiovascular benefits were limited:

• No reduction in major adverse cardiovascular events (HR 0.90,95% CI 0.78-1.04) 1
• Reduction in nonfatal myocardial infarction (HR 0.76,95% CI 0.62-0.92) 1
• No reduction in fatal or nonfatal stroke 1
• No reduction in congestive heart failure 1

Microvascular Outcomes

Intensive therapy did NOT reduce clinical microvascular events including loss of vision, end-stage renal disease, or painful neuropathy. 1 The only microvascular benefit was small absolute reductions in surrogate endpoints like onset of albuminuria. 1, 3

Extended follow-up through median 5 years confirmed these findings, with achieved HbA1c levels of 7.2% in the intensive group versus 7.6% in the standard group. 1

Current Guideline Recommendations Based on ACCORD

The American College of Physicians (2018) recommends:

• Target HbA1c range of 7-8% for most patients with type 2 diabetes 1
• Consider deintensifying pharmacologic therapy for patients achieving HbA1c <6.5% 1, 4
• Avoid targeting HbA1c levels below 6.5%, as no trials demonstrate improved clinical outcomes at these levels 1, 4, 5

The American Diabetes Association (2023) recommends:

• Less stringent targets (HbA1c up to 8%) may be appropriate for patients with: 1
  • Long duration of diabetes
  • History of severe hypoglycemia
  • Advanced atherosclerosis
  • Advanced age or frailty
  • Limited life expectancy (<10 years)

Who Is at Highest Risk from Intensive Control

Patients most likely to experience harm from intensive glycemic control (HbA1c <6.5%): 1

• Established cardiovascular disease
• Long diabetes duration (>8-11 years)
• Older age (>60 years)
• History of hypoglycemia
• Advanced atherosclerosis
• Frailty or limited life expectancy

Practical Algorithm for HbA1c Target Selection

For patients with type 2 diabetes and cardiovascular disease or high cardiovascular risk:

1. Target HbA1c 7-8% as the standard approach 1

2. Consider HbA1c <7% (but not <6.5%) ONLY if: 1

   • Short diabetes duration (<5 years)
   • Long life expectancy (>15 years)
   • No history of cardiovascular disease
   • Can be achieved safely without hypoglycemia, weight gain, or polypharmacy

3. Target HbA1c 7.5-8% for: 1

   • Diabetes duration >10 years
   • Known cardiovascular disease
   • History of severe hypoglycemia
   • Age >65 years
   • Limited life expectancy

4. Deintensify therapy if HbA1c falls below 6.5% 1, 4

Critical Pitfalls to Avoid

Never target HbA1c below 6.5% in patients with established type 2 diabetes and cardiovascular disease. The ACCORD trial definitively demonstrated increased mortality with this approach. 1

Recognize that insulin deficiency and islet autoantibodies predict severe hypoglycemia during intensive treatment. Patients with fasting C-peptide ≤0.15 nmol/L had 23-fold increased odds of severe hypoglycemia with inability to achieve target HbA1c. 6

Understand that microvascular benefits are limited to surrogate endpoints. ACCORD showed no reduction in clinical microvascular outcomes like vision loss, end-stage renal disease, or painful neuropathy. 1, 3

Special Populations

In patients with heart failure and diabetes: Observational data suggest HbA1c <7% may be associated with increased mortality compared to HbA1c 7-8%. 1 The ACCORD subgroup with heart failure at baseline showed no differential mortality effect, but the overall increased mortality signal warrants caution. 1

In newly diagnosed diabetes: The UKPDS demonstrated long-term cardiovascular benefits with achieved HbA1c of 7.0% (not below 6.5%), particularly with metformin in overweight patients. 1 This contrasts sharply with ACCORD's findings in established disease.

Medication Deintensification Strategy

For patients with HbA1c <6.5% on multiple agents: 4

• Discontinue medications gradually, starting with highest hypoglycemia risk agents (insulin, sulfonylureas)
• Monitor glucose levels more frequently during transition
• Recheck HbA1c in 3-6 months
• Maintain lifestyle modifications

Durable glycemic control is achievable: Patients who achieved HbA1c <6.5% during intensive ACCORD treatment maintained better control even after therapy relaxation, particularly those with greater BMI reduction and medication deintensification. 7