What are the implications of the Accord trial on glucose control targets and treatment for type 2 diabetes?

ACCORD Trial Implications for Type 2 Diabetes Management

Critical Finding: Intensive Glycemic Control Increases Mortality in High-Risk Patients

The ACCORD trial demonstrated that targeting HbA1c <6.0% in patients with established type 2 diabetes and cardiovascular disease resulted in a 22% increase in all-cause mortality (HR 1.22,95% CI 1.01-1.46) compared to standard targets of 7.0-7.9%, leading to early trial termination. 1

Key Trial Characteristics That Define When Intensive Control Is Harmful

The ACCORD trial enrolled 10,251 participants with specific high-risk features that clinicians must recognize 1:

• Mean age 62 years with mean diabetes duration of 10 years 1
• Established cardiovascular disease or multiple cardiovascular risk factors 1
• Baseline median HbA1c of 8.1% with 35% already using insulin 1
• Intensive arm achieved HbA1c of 6.4% within 12 months versus 7.5% in standard arm 1

Mortality and Cardiovascular Outcomes

The mortality signal persisted throughout follow-up 2:

• Annual mortality rate: 1.41% (intensive) vs 1.14% (standard) 1
• Cardiovascular deaths were similarly increased in the intensive group 1
• Severe hypoglycemia increased 3-fold with intensive control 3
• Despite increased mortality, nonfatal myocardial infarction was reduced (HR 0.79,95% CI 0.66-0.95), though this benefit was offset by mortality 2

Importantly, no clear mechanism for excess mortality was identified despite extensive analysis of hypoglycemia, weight gain, specific drug combinations, and rate of HbA1c reduction 1.

Recommended HbA1c Targets Based on ACCORD

For patients with long-standing type 2 diabetes (≥8-10 years duration), established cardiovascular disease, or multiple cardiovascular risk factors, target HbA1c of 7.0-8.0% 1, 3. The American College of Physicians specifically recommends 7-8% for most patients with type 2 diabetes 3.

Avoid HbA1c targets <6.5% in patients with: 1, 3

• Long diabetes duration (>8-10 years)
• Known history of severe hypoglycemia
• Advanced atherosclerosis or established cardiovascular disease
• Advanced age or frailty
• Limited life expectancy (<10 years)

Microvascular Benefits Still Exist But Are Modest

Despite the mortality signal, ACCORD showed some microvascular benefits 4:

• Delayed onset of albuminuria (HR 0.79,95% CI 0.72-0.87) 4
• Some measures of eye complications improved (7 of 13 secondary measures favored intensive therapy, p<0.05) 4
• However, no reduction in advanced microvascular outcomes (dialysis, renal transplantation, or retinal photocoagulation) occurred 4

These modest microvascular benefits must be weighed against the 22% increase in mortality 1, 4.

Contrast with ADVANCE and VADT Trials

The ADVANCE trial achieved similar HbA1c levels (6.5% vs 7.3%) but showed no mortality increase, likely because 1:

• Participants had 2-3 years shorter diabetes duration
• Less insulin use at baseline (very little vs 35% in ACCORD)
• More gradual HbA1c reduction without significant weight gain
• Lower rates of severe hypoglycemia (<3% over 5 years vs 16% in ACCORD)

The VADT showed no mortality benefit or harm at 10-year follow-up, with reduction in cardiovascular events but not mortality 1.

When Intensive Control May Be Appropriate

HbA1c <7.0% may be considered only in patients with: 1, 3

• Short diabetes duration (<5 years from diagnosis)
• No history of cardiovascular disease
• Long life expectancy (>10-15 years)
• Ability to achieve target safely without hypoglycemia or significant weight gain
• Younger age without frailty

This recommendation is supported by UKPDS long-term follow-up showing cardiovascular benefits emerged only after 10 years in newly diagnosed patients with achieved HbA1c of 7.0% (not <6.5%) 1, 3.

Clinical Algorithm for Target Selection

Step 1: Assess diabetes duration

• If ≥8-10 years → Target HbA1c 7.0-8.0% 1, 3
• If <5 years → Consider HbA1c <7.0% if other criteria met 1, 3

Step 2: Assess cardiovascular disease status

• If established CVD or multiple risk factors → Target HbA1c 7.0-8.0% 1, 3
• If no CVD → Proceed to Step 3

Step 3: Assess hypoglycemia risk

• If history of severe hypoglycemia → Target HbA1c 7.0-8.0% 1
• If no history and low risk → Consider HbA1c <7.0% 3

Step 4: Assess age and frailty

• If age >65 years or frail → Target HbA1c 7.0-8.0% 1
• If younger and robust → Consider HbA1c <7.0% 3

Critical Pitfall to Avoid

Do not aggressively lower HbA1c in patients already at HbA1c <6.5% 3. The mortality risk appears related to the treatment strategy and intensity, not the achieved HbA1c per se 1. Patients who easily maintain low HbA1c with lifestyle or minimal medication do not need to "raise" their HbA1c 1.

Deintensification Strategy

For patients with HbA1c <6.5% on intensive regimens, consider deintensifying therapy 3, particularly if they have:

• Multiple glucose-lowering medications
• Insulin therapy with frequent dosing adjustments
• History of hypoglycemia
• Long diabetes duration with cardiovascular disease