What happens when your glycohemoglobin (HbA1c) is elevated?

Elevated Glycohemoglobin (HbA1c): Implications and Consequences

Elevated glycohemoglobin (HbA1c) indicates chronic hyperglycemia and significantly increases the risk of microvascular and macrovascular complications including retinopathy, nephropathy, neuropathy, and cardiovascular disease. 1

Understanding HbA1c

• HbA1c forms when glucose attaches to the N-terminal valine residue of the hemoglobin β-chain, creating a stable ketoamine through an irreversible Amadori rearrangement 1
• HbA1c reflects average blood glucose levels over the previous 2-3 months, with recent glycemia having greater influence (50% from the past month, 25% from 30-60 days prior, and 25% from 60-120 days prior) 1
• Each 1% increase in HbA1c corresponds to approximately 35 mg/dL (2 mmol/L) increase in mean plasma glucose 1

Health Consequences of Elevated HbA1c

Microvascular Complications

• Retinopathy: The Diabetes Control and Complications Trial (DCCT) demonstrated that elevated HbA1c increases retinopathy risk, with a 76% reduction in new retinopathy development when HbA1c was reduced by 1.8% 1
• Nephropathy: Elevated HbA1c increases risk of microalbuminuria (39% reduction with improved control) and progression to diabetic kidney disease 1
• Neuropathy: Higher HbA1c levels are associated with 60% increased risk of developing clinical neuropathy 1

Macrovascular Complications

• Cardiovascular disease: Elevated HbA1c is associated with increased risk of cardiovascular events and mortality 1
• In patients with end-stage kidney disease, HbA1c levels ≥10% were associated with 41% higher all-cause mortality and 73% higher cardiovascular mortality compared to levels of 5-6% 1

U-shaped Mortality Risk

• Both very high (>8.5%) and very low (<6%) HbA1c levels are associated with increased mortality risk, particularly in patients with advanced chronic kidney disease 1
• A meta-analysis of hemodialysis patients showed a U-shaped mortality curve with lowest risk at moderate HbA1c levels 1

Pathophysiological Mechanisms

• Chronic hyperglycemia causes glucose toxicity through multiple pathways 2, 3:
  • Increased oxidative stress and inflammatory mediators 1
  • Tissue damage to pancreatic β-cells (reducing insulin production) 2
  • Vascular endothelial cell damage 2
  • Formation of advanced glycation end-products (AGEs) 3

Special Considerations and Confounding Factors

• Hemoglobin variants (e.g., HbS, HbC) can interfere with HbA1c measurements, causing falsely high or low results 1
• Conditions affecting red blood cell lifespan alter HbA1c independent of glycemia 1:
  • Shortened RBC lifespan (kidney disease, liver disease, hemolytic anemia, pregnancy) decreases HbA1c
  • Prolonged RBC lifespan (iron deficiency anemia, aplastic anemia) increases HbA1c
• Uremia can cause falsely elevated HbA1c through formation of carbamylated hemoglobin 1, 4
• High-dose salicylates can form acetylated hemoglobin, affecting results 1

Clinical Targets and Management

• For most adults with diabetes, HbA1c targets of <7% are recommended to reduce microvascular complications 1, 5
• Higher targets (>7%) may be appropriate for patients with history of severe hypoglycemia, limited life expectancy, advanced complications, or certain comorbidities 1, 5
• HbA1c levels ≥9% represent a high-risk state that should be addressed promptly 5
• In patients with advanced chronic kidney disease, extreme HbA1c targets (<6.5% or >11%) are associated with increased mortality risk 1

Monitoring Recommendations

• Regular HbA1c testing is recommended for all patients with diabetes 1
• Testing frequency should be at least twice yearly for patients meeting treatment goals with stable glycemic control 1
• Quarterly assessment is recommended for patients whose therapy has changed or who are not meeting glycemic goals 1
• When HbA1c results seem discordant with clinical picture, consider potential confounding factors and alternative monitoring methods 1, 4

Elevated HbA1c reflects a pathological state of chronic hyperglycemia that causes progressive damage to multiple organ systems through various biochemical pathways. Early identification and management of elevated HbA1c is essential to prevent or delay the development of serious diabetes-related complications.