How can a patient with a borderline prediabetic glycated hemoglobin (HbA1c) have a favorable metabolic profile, low fasting insulin, and a favorable lipid profile?

HbA1c 5.6% with Favorable Metabolic Markers: Understanding the Discordance

An HbA1c of 5.6% with healthy fasting insulin and favorable lipid ratios reflects the well-documented discordance between HbA1c and other metabolic markers, where HbA1c captures only glycemic exposure over 2-3 months but fails to identify underlying insulin resistance, dyslipidemia, or inflammatory states that drive cardiometabolic risk. 1, 2

Why This Discordance Occurs

HbA1c Measures Only One Dimension of Metabolic Health

• HbA1c reflects time-averaged glucose over the preceding 2-3 months and correlates specifically with microvascular complications like retinopathy, but it does not capture insulin resistance, lipid metabolism, or inflammatory markers that determine cardiovascular risk 1, 2

• The prediabetes threshold of 5.7-6.4% was set to identify individuals at high risk for progression to diabetes, not to identify all individuals with adverse metabolic profiles 1, 2

• Research demonstrates that HbA1c alone is a poor indicator of cardiometabolic risk in middle-aged subjects with prediabetes, as individuals diagnosed by fasting plasma glucose show stronger associations with diabetes-related phenotypes than those identified by HbA1c alone 3

Insulin Resistance and Glycemia Are Not Perfectly Correlated

• Early insulin resistance can exist with normal or near-normal glucose levels because compensatory hyperinsulinemia maintains euglycemia until beta-cell function declines 3, 4

• Your patient's low fasting insulin suggests preserved beta-cell function and good insulin sensitivity, meaning glucose disposal is efficient despite the borderline HbA1c 3

• Studies show that individuals with impaired fasting glucose (IFG) have higher HOMA-IR values than those with impaired glucose tolerance (IGT), indicating that different pathophysiological processes underlie these conditions 4

Lipid Profile Reflects Different Metabolic Pathways

• A favorable triglyceride/HDL ratio indicates good hepatic insulin sensitivity and low visceral adiposity, which are independent of glycemic control 2, 3

• The triglyceride-glucose (TyG) index, which combines fasting glucose and triglycerides, may be more sensitive than HbA1c alone for detecting metabolic dysfunction, but your patient's favorable lipids suggest this index would also be reassuring 5

• Metabolic syndrome features (hypertension, dyslipidemia, central obesity) are more strongly associated with cardiovascular risk than HbA1c alone in the prediabetic range 3, 4

The Continuum of Risk Concept

HbA1c Thresholds Are Somewhat Arbitrary

• The 5.7% cutoff for prediabetes was chosen to balance sensitivity and specificity for predicting future diabetes, not because it represents a sharp biological threshold 1, 2

• The American Diabetes Association acknowledges that "the risk of diabetes with any measure of glycemia is a continuum, extending well into the normal ranges" 1

• Individuals with HbA1c 5.5-6.0% have a 5-year cumulative diabetes incidence of 12-25%, which is 3-8 fold higher than the general population, but this still means 75-88% will NOT develop diabetes 1

Your Patient's Position on the Risk Spectrum

• An HbA1c of 5.6% corresponds to an estimated average glucose of approximately 114 mg/dL (range 100-128 mg/dL), which is only marginally elevated 2

• Linear regression analyses indicate that an FPG of 100 mg/dL corresponds to an HbA1c of 5.4%, so 5.6% suggests an FPG around 105-110 mg/dL—barely above the normal threshold 1

• Your patient is only 0.1% from the prediabetes threshold because the cutoff is arbitrary, not because they have clinically significant metabolic dysfunction 1, 2

Clinical Implications and Pitfalls

Do Not Over-Interpret Borderline HbA1c Values

• HbA1c screening identifies only about 50-53% of individuals with abnormal oral glucose tolerance tests in Caucasian populations, demonstrating substantial discordance between these measures 3, 4

• Patients with prediabetes diagnosed by both HbA1c AND fasting glucose have worse metabolic profiles (OR 4.0 for ≥3 metabolic syndrome features) than those identified by either test alone 3

• Your patient's favorable insulin and lipid markers suggest they are NOT in the high-risk subset despite the borderline HbA1c 3, 4

Consider the Whole Metabolic Picture

• Cardiovascular risk in prediabetes is driven more by lipid abnormalities, hypertension, and inflammation than by glycemia alone 1, 3

• The American Heart Association emphasizes that "less stringent HbA1c goals may be appropriate" when considering the totality of metabolic risk factors 1

• Smoking cessation is prioritized over glycemic control for preventing macrovascular complications in prediabetic patients, highlighting that HbA1c is not the dominant risk factor 6

Practical Management Approach

Risk Stratification Based on Multiple Markers

• Recheck HbA1c in 3-6 months to confirm stability and rule out laboratory variation 6

• Obtain a fasting glucose and consider an oral glucose tolerance test if clinical suspicion for diabetes remains high, as HbA1c may miss up to 50% of cases 3, 4

• Continue monitoring lipids, blood pressure, and waist circumference as these are stronger predictors of cardiovascular outcomes than borderline HbA1c 3, 4

Lifestyle Intervention Remains First-Line

• Intensive lifestyle modification targeting ≥7% weight reduction and ≥150 minutes/week of moderate-intensity activity is recommended for all individuals with HbA1c 5.7-6.4%, regardless of other metabolic markers 6

• Your patient's favorable metabolic profile suggests they may be responding well to lifestyle measures or have genetic protection against metabolic dysfunction 3, 4

Avoid Premature Pharmacologic Intervention

• Metformin is recommended for prediabetes only when BMI ≥25 kg/m² AND lifestyle intervention fails to achieve weight loss goals, not based on HbA1c alone 6

• GLP-1 receptor agonists are considered when obesity is present (BMI ≥30 kg/m²) and cardiovascular risk factors accumulate, but your patient's favorable profile does not mandate immediate pharmacotherapy 6

Key Takeaway

The apparent paradox of borderline HbA1c with favorable metabolic markers reflects the biological reality that HbA1c is only one component of metabolic health, and the 5.7% prediabetes threshold is a screening tool—not a definitive marker of disease. Your patient's low fasting insulin and good triglyceride/HDL ratio indicate preserved insulin sensitivity and favorable cardiovascular risk, which are more clinically meaningful than being 0.1% below an arbitrary diagnostic cutoff. 1, 2, 3, 4