What happens when HbA1c is high?

High HbA1c and Its Implications for Health

Elevated glycohemoglobin (HbA1c) significantly increases the risk of microvascular complications including retinopathy, nephropathy, and neuropathy, with risk accelerating when levels exceed 9%. 1, 2

Understanding HbA1c and Its Significance

• HbA1c is a valuable biomarker that reflects average blood glucose levels over the preceding 2-3 months, with approximately 50% representing the most recent month, 25% from 30-60 days prior, and 25% from 60-120 days prior 3
• Each 1% increase in HbA1c corresponds to an approximate increase in mean plasma glucose of 35 mg/dL (2 mmol/L) 3
• HbA1c serves as the primary index for assessing long-term glycemic control and correlates directly with the development of diabetes complications 4, 1

Health Consequences of Elevated HbA1c

Microvascular Complications

• The relationship between HbA1c and risk for microvascular complications is continuous and accelerates significantly when levels exceed 9% 3
• Higher HbA1c levels are associated with increased risk of diabetic retinopathy, chronic kidney disease, and cardiovascular disease 2
• In patients with diabetes, elevated HbA1c increases the risk of developing new retinopathy, microalbuminuria, and clinical neuropathy 3

Cardiovascular Risk

• Elevated HbA1c is considered an independent risk factor for coronary heart disease and stroke in individuals with or without diabetes 1
• A meta-analysis showed that each 1% higher glycosylated hemoglobin level was associated with an 18% increased risk for cardiovascular disease in patients with type 2 diabetes (pooled RR 1.18,95% CI 1.10-1.26) 3

Mortality Risk

• In patients with end-stage kidney disease (ESKD), HbA1c levels ≥10% are associated with significantly higher all-cause mortality (HR 1.41,95% CI 1.25-1.60) and cardiovascular death (HR 1.73,95% CI 1.44-2.08) compared to HbA1c levels in the 5-6% range 3
• In hemodialysis patients, a U-shaped association between HbA1c and mortality has been observed, with higher mortality for levels <6% and ≥9% 3

Special Considerations in Chronic Kidney Disease

• Risk of hypoglycemia is amplified in patients with CKD, especially if kidney function is substantially reduced (CKD stages 4 and 5) 3
• Patients with advanced CKD face increased hypoglycemia risk due to decreased clearance of insulin and some oral agents, as well as impaired renal gluconeogenesis 3
• Patients with type 1 diabetes who have significant creatinine elevations experience a 5-fold increase in severe hypoglycemia frequency 3

Interpreting HbA1c Results: Important Caveats

• Several conditions can affect HbA1c measurement accuracy independent of glycemic control 3, 5:
  • Hemoglobin variants (e.g., Hemoglobin S or C) can cause spuriously high or low results 3
  • Conditions that shorten erythrocyte lifespan (kidney disease, liver disease, hemolytic anemia, hemoglobinopathies) decrease HbA1c 3
  • Iron-deficiency anemia can falsely increase HbA1c 3
  • Conditions that slow erythropoiesis (e.g., aplastic anemia) increase HbA1c 3

Treatment Targets Based on HbA1c

• For most patients with diabetes, an HbA1c target of ≤7% is beneficial for reducing microvascular complications 3
• For patients at risk of hypoglycemia (those on insulin or sulfonylureas, or with advanced CKD), treating to an HbA1c target <7.0% is not recommended 3
• In patients with comorbidities or limited life expectancy (<10 years), higher HbA1c target ranges (7.0-8.0% or 7.5-8.5%) are appropriate 3
• For individuals with major comorbidities that decrease life expectancy (<5 years) or advanced microvascular complications, even higher HbA1c targets may be justified 3

Clinical Approach to Elevated HbA1c

• When HbA1c is elevated, first verify the accuracy of the measurement, considering potential confounding factors 3, 5
• For patients with elevated HbA1c, assess for presence of complications through appropriate screening for retinopathy, nephropathy, and neuropathy 2
• Implement a multifactorial approach to management including medications, proper nutrition, meal planning, and physical activity, with modifications as needed for CKD 3
• Monitor for hypoglycemia risk, especially in patients with advanced CKD, as they may require dose adjustments of insulin or oral agents 3