The ACCORD trial of intensive glycaemic control (HbA1c target <6%) in type 2 diabetes was terminated early due to excess cardiovascular mortality in the intensive arm. Which pathophysiological mechanism is most implicated in this finding?

• A Increased LDL oxidation from tight glucose control
• B Higher insulin doses promoting endothelial dysfunction
• C Increased HbA1c fluctuation causing platelet activation
• D Severe hypoglycaemia triggering arrhythmia and cardiovascular events ✓

Explanation

The ACCORD trial demonstrated higher all-cause and cardiovascular mortality in the intensive arm, largely attributed to severe hypoglycaemia triggering adrenergic surges, QTc prolongation, and fatal arrhythmias, particularly in patients with established cardiovascular disease. The ADVANCE trial found no excess mortality with similar targets, suggesting baseline CV risk modifies the harm. This informs current guidelines recommending individualised HbA1c targets of 7–8% in high-risk patients.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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