What is the management approach for a patient with low Hemoglobin A1C (HbA1C) and glucosuria?

Management of Low A1C with Glucosuria

The combination of low HbA1c with glucosuria suggests either an SGLT2 inhibitor effect, renal glycosuria, or a condition affecting red blood cell turnover—you must first determine if the patient is on an SGLT2 inhibitor, as this is the expected pharmacologic effect, and if not, investigate for renal tubular disorders or hemolytic conditions. 1

Initial Diagnostic Approach

Medication Review

• Immediately verify if the patient is taking an SGLT2 inhibitor (canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin), as these medications intentionally cause glucosuria by blocking renal glucose reabsorption, which can lower HbA1c by 0.5-1% while producing persistent glucosuria. 2

• If on an SGLT2 inhibitor, the low HbA1c with glucosuria is the expected therapeutic effect and requires no intervention beyond standard monitoring. 2

Assess for Hypoglycemia Risk

• Evaluate for frequent hypoglycemic episodes using continuous glucose monitoring (CGM) or increased self-monitoring of blood glucose, as recurrent hypoglycemia can artificially lower HbA1c while causing intermittent hyperglycemia with glucosuria. 1

• Check for hypoglycemia unawareness, particularly in patients using insulin or sulfonylureas, as this represents a critical safety concern requiring immediate medication adjustment. 3, 1

Evaluate HbA1c Reliability

• Consider conditions that falsely lower HbA1c: recent blood transfusions, hemolytic anemia, chronic kidney disease (especially with erythropoietin use), or any condition shortening red blood cell lifespan. 3, 1

• In advanced CKD (eGFR <30 mL/min/1.73 m²), HbA1c becomes unreliable due to anemia, erythropoietin-stimulating agents, and reduced erythrocyte lifespan—supplement with CGM or self-monitoring of blood glucose. 3

Specific Clinical Scenarios

If Patient is NOT on SGLT2 Inhibitor

Investigate for renal glycosuria:

• Measure fasting plasma glucose and perform glucose tolerance testing to determine if glucosuria occurs at normal blood glucose levels (renal threshold <180 mg/dL). 3

• Renal glycosuria is a benign condition requiring no treatment but explains the discordance between low HbA1c and glucosuria. 3

Evaluate for conditions affecting RBC turnover:

• Order complete blood count, reticulocyte count, and peripheral smear to assess for hemolytic anemia or other hematologic conditions. 1

• Consider glycated albumin or fructosamine as alternative glycemic markers if RBC turnover is abnormal, though these have limitations in CKD and hypoalbuminemia. 3

If Patient Has Diabetes with Low HbA1c (<6%)

Assess hypoglycemia burden:

• Deploy CGM for 10-14 days to quantify time below range (<70 mg/dL and <54 mg/dL), as this provides the most accurate assessment of hypoglycemia frequency and severity. 1

• If time below range >4% or any time <54 mg/dL, deintensify therapy immediately by reducing insulin doses or discontinuing sulfonylureas. 3, 1

Medication adjustment strategy:

• For patients with HbA1c <6.5% and evidence of hypoglycemia, reduce or discontinue insulin secretagogues (sulfonylureas) first, as these carry the highest hypoglycemia risk. 1

• Reduce basal insulin by 10-20% and reassess in 1-2 weeks if hypoglycemia is documented. 1

• Consider switching to medications with lower hypoglycemia risk (GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors) if glycemic control permits. 3

Special Population: Advanced CKD

In patients with eGFR <30 mL/min/1.73 m²:

• Do not rely on HbA1c alone for glycemic assessment—the combination of anemia, erythropoietin use, and shortened RBC lifespan renders HbA1c unreliable and typically falsely low. 3

• Use CGM metrics (time in range 70-180 mg/dL, time below range) as the primary glycemic assessment tool in dialysis patients. 1, 4

• Target HbA1c 7-8% in advanced CKD, recognizing that measured values may underestimate true glycemia. 3, 4

Monitoring Strategy

If Low HbA1c is Appropriate (No Hypoglycemia)

• Continue current management if patient has good quality of life, no hypoglycemia symptoms, and CGM confirms time in range >70% with time below range <4%. 1

• Monitor for development of hypoglycemia unawareness by asking about diminished autonomic symptoms during low blood glucose episodes. 3

• Reassess HbA1c every 3 months and correlate with blood glucose measurements or CGM data. 1

If Hypoglycemia is Present

• Increase glycemic targets to HbA1c 7-8% for patients with advanced age, multiple comorbidities, limited life expectancy, or history of severe hypoglycemia. 3

• Implement a 2-4 week period of strict hypoglycemia avoidance (glucose targets 100-180 mg/dL) to partially restore hypoglycemia awareness. 3

Critical Pitfalls to Avoid

• Never assume low HbA1c represents excellent control without verifying absence of hypoglycemia—use CGM or frequent self-monitoring to confirm. 1

• Do not target HbA1c <6% in older adults, those with limited life expectancy, or patients with hypoglycemia unawareness, as risks outweigh benefits. 3

• Do not ignore glucosuria in non-diabetic patients—this may represent renal glycosuria, Fanconi syndrome, or other tubular disorders requiring nephrology evaluation. 3

• In CKD stage 4-5, do not use HbA1c as the sole glycemic metric—supplement with glucose monitoring or alternative markers. 3, 4

• Do not continue aggressive glucose-lowering therapy in patients with HbA1c <6.5% and documented hypoglycemia—deintensification is mandatory. 3, 1