A patient with type 2 diabetes on empagliflozin (Jardiance) 25 mg daily has hemoglobin A1c increased from 5.7% to 6.2%; how should I manage this?

Management of Rising HbA1c on Empagliflozin 25 mg

Continue empagliflozin 25 mg and add metformin as foundational therapy, titrating to 2000 mg daily, then reassess in 3 months and add a GLP-1 receptor agonist if HbA1c remains above 7%.

Current Glycemic Status Assessment

Your patient's HbA1c has risen from 5.7% to 6.2% while on empagliflozin (Jardiance) 25 mg monotherapy. While 6.2% remains below the standard target of <7% for most adults 1, this upward trajectory of 0.5% indicates progressive loss of glycemic control that warrants treatment intensification rather than observation 2.

• An HbA1c increase from 5.7% to 6.2% represents a clinically meaningful change that signals the need for medication adjustment 1
• The current value of 6.2% falls into the prediabetes-to-early diabetes range, where intervention can prevent further deterioration 2

Why Empagliflozin Alone Is Insufficient

Empagliflozin 25 mg monotherapy typically reduces HbA1c by 0.5–0.8% from baseline 3, 4. Your patient's rising HbA1c despite maximum-dose empagliflozin indicates that:

• SGLT2 inhibitor monotherapy cannot maintain adequate glycemic control in this patient 2
• The progressive nature of type 2 diabetes requires combination therapy to achieve durable control 2
• Empagliflozin provides crucial cardiovascular and renal protection independent of glucose lowering, so it must be continued 5

Recommended Treatment Algorithm

Step 1: Add Metformin Immediately

Initiate metformin 500 mg once or twice daily with meals, increasing by 500 mg weekly to a target of 2000 mg daily (1000 mg twice daily). 2

• Metformin is the foundational therapy for type 2 diabetes and should be started unless contraindicated (eGFR <30 mL/min/1.73 m²) 2
• The combination of empagliflozin + metformin provides complementary mechanisms: SGLT2 inhibition plus reduced hepatic glucose production and enhanced insulin sensitivity 6
• Initial combination therapy with empagliflozin + metformin reduces HbA1c by 1.9–2.1% from baseline, significantly more than either agent alone 6
• Metformin carries minimal hypoglycemia risk, offers cardiovascular mortality benefit, and is weight-neutral 2

Step 2: Reassess at 3 Months

Measure HbA1c after 3 months of optimized metformin + empagliflozin therapy. 2

• If HbA1c is <7%, continue current regimen and monitor every 6 months 2
• If HbA1c remains ≥7%, proceed to Step 3 2

Step 3: Add GLP-1 Receptor Agonist if Needed

If HbA1c remains ≥7% after 3 months, add a GLP-1 receptor agonist (semaglutide, liraglutide, or dulaglutide) as the third agent. 2

• GLP-1 receptor agonists provide an additional 0.6–0.8% HbA1c reduction when added to metformin + SGLT2 inhibitor therapy 2
• They promote weight loss of 2–5 kg rather than weight gain 2
• GLP-1 receptor agonists have proven cardiovascular benefit in patients with or at high risk for cardiovascular disease 2
• They carry minimal hypoglycemia risk when not combined with sulfonylureas or insulin 2

Why This Approach Is Superior to Alternatives

Do Not Wait and Observe

• Therapeutic inertia—delaying treatment intensification—increases exposure to hyperglycemia and raises complication risk 2
• The 3-month reassessment window is the maximum acceptable interval before escalating therapy 2

Do Not Switch Empagliflozin to Another Agent

• Empagliflozin provides cardiovascular and renal protection independent of its glucose-lowering effect 5
• The EMPA-REG OUTCOME trial demonstrated a 38% reduction in cardiovascular death and 32% reduction in all-cause mortality 5
• These benefits persist even when HbA1c is at goal, making empagliflozin continuation essential 2

Do Not Add Sulfonylureas

• Sulfonylureas increase hypoglycemia risk markedly, especially in older adults 2
• They lack the cardiovascular and weight benefits of GLP-1 receptor agonists 2
• Sulfonylureas should be avoided when safer, more effective alternatives exist 2

Do Not Add DPP-4 Inhibitors

• DPP-4 inhibitors provide only modest HbA1c reduction (0.5–0.8%) and lack proven cardiovascular mortality benefit 2
• GLP-1 receptor agonists are superior to DPP-4 inhibitors in treatment hierarchies for patients with or at risk for cardiovascular disease 2

Monitoring and Safety

• Check eGFR before starting metformin and annually thereafter; metformin is contraindicated when eGFR <30 mL/min/1.73 m² 2
• Monitor for vitamin B12 deficiency with long-term metformin use, especially if anemia or peripheral neuropathy develop 2
• Educate the patient on signs of euglycemic diabetic ketoacidosis with empagliflozin (nausea, vomiting, abdominal pain, dyspnea) 2
• Reassess HbA1c every 3 months until target is achieved, then every 6 months once stable 2

Expected Outcomes

• Metformin addition is expected to reduce HbA1c by 0.9–1.1%, potentially achieving target <7% 2
• If a third agent is needed, the triple combination (empagliflozin + metformin + GLP-1 RA) typically achieves HbA1c reductions of 2–3% from baseline 2
• Weight loss of 2–5 kg is expected with GLP-1 receptor agonist addition 2
• Cardiovascular and renal protection is maximized by maintaining empagliflozin throughout intensification 5

Critical Pitfalls to Avoid

• Do not discontinue empagliflozin when adding other agents; it provides organ-protective benefits independent of glucose lowering 2, 5
• Do not delay metformin initiation while waiting to see if empagliflozin alone will suffice; the rising HbA1c indicates monotherapy failure 2
• Do not skip the 3-month reassessment; prolonged inertia increases complication risk 2
• Do not combine GLP-1 receptor agonists with DPP-4 inhibitors if a third agent is needed; no additional benefit is observed 2