What is the most appropriate long-term glucose-lowering therapy for a patient with type 2 diabetes (T2D), on metformin (biguanide) 1g twice daily (BD) and empagliflozin (SGLT2 inhibitor) 25mg daily, following a ketogenic diet, with a history of euglycemic diabetic ketoacidosis (EDKA) and recent episode of gastroenteritis, now with impaired glycemic control (HbA1c 8.7%) and seeking to avoid weight gain?

Most Appropriate Long-Term Glucose-Lowering Therapy

The most appropriate long-term therapy is metformin monotherapy with the addition of a GLP-1 receptor agonist (such as semaglutide or liraglutide), while permanently discontinuing empagliflozin due to the recent euglycemic diabetic ketoacidosis.

Immediate and Permanent Discontinuation of SGLT2 Inhibitor

Empagliflozin must be permanently discontinued and never restarted given this patient's documented euglycemic diabetic ketoacidosis (EDKA), which represents an absolute contraindication to future SGLT2 inhibitor use 1, 2, 3, 4, 5.

• The combination of empagliflozin with a ketogenic diet created a perfect storm for EDKA, as both independently promote ketogenesis 4.
• EDKA can recur up to 2 weeks after the last dose of empagliflozin due to persistent glucosuria and ketonuria, even with serum glucose below the renal threshold 1.
• The risk factors present in this patient—ketogenic diet, reduced oral intake from gastroenteritis, and SGLT2 inhibitor use—represent a critical trio that precipitated the life-threatening metabolic decompensation 4.

Optimal Long-Term Regimen: Metformin Plus GLP-1 Receptor Agonist

Continue metformin 1g BD as the foundation of therapy and add a GLP-1 receptor agonist to address the inadequate glycemic control (HbA1c 8.7%) while avoiding weight gain 6.

Why GLP-1 Receptor Agonists Are Ideal for This Patient

• GLP-1 receptor agonists are the preferred injectable therapy for type 2 diabetes requiring treatment intensification, offering superior outcomes compared to insulin in terms of weight management 6.
• These agents provide HbA1c reductions of 0.6-0.8% when added to metformin, with the additional benefit of weight loss rather than weight gain 6, 7.
• Semaglutide 2.4mg weekly achieves 14.9% weight loss at 68 weeks, making it particularly appropriate for patients seeking to avoid weight gain 7.
• GLP-1 receptor agonists have minimal hypoglycemia risk when used without sulfonylureas or insulin, addressing safety concerns after this patient's recent metabolic crisis 7.

Specific GLP-1 Receptor Agonist Selection

Semaglutide (starting at 0.25mg weekly, titrating to 1.0-2.4mg weekly) or liraglutide (starting at 0.6mg daily, titrating to 1.8-3.0mg daily) represent the best options 7.

• Both agents require no dose adjustment across all stages of chronic kidney disease, including this patient's eGFR of 68 mL/min/1.73m² 7.
• Semaglutide offers once-weekly dosing convenience and proven cardiovascular benefits with a 26% reduction in cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.74,95% CI 0.58-0.95) 7.
• The slow titration schedule minimizes gastrointestinal adverse effects, which are typically mild-to-moderate and transient 7.

Why Other Options Are Inappropriate

SGLT2 Inhibitors (Including Empagliflozin)

Absolutely contraindicated due to documented EDKA 1, 2, 3, 4, 5.

Insulin Therapy

• Insulin causes weight gain, directly contradicting the patient's stated goal of avoiding weight gain 6.
• The combination of insulin with metformin is effective but results in more weight gain than GLP-1 receptor agonist combinations 6.

DPP-4 Inhibitors

• These agents are weight-neutral but provide inferior HbA1c reduction (typically <1%) compared to GLP-1 receptor agonists 6.
• When combined with insulin, SGLT2 inhibitors showed greater HbA1c reduction and weight advantages compared to DPP-4 inhibitors 6.

Sulfonylureas

• These agents cause weight gain and significantly increase hypoglycemia risk, making them inappropriate for this patient 6.

Critical Dietary Counseling Required

The ketogenic diet must be discontinued or significantly modified to prevent recurrent ketoacidosis, even without SGLT2 inhibitor use 4.

• The patient should be counseled that the combination of a ketogenic diet with diabetes medications that promote ketogenesis (like SGLT2 inhibitors) creates dangerous metabolic conditions 4.
• A balanced, reduced-calorie diet with adequate carbohydrate intake (500-kcal deficit below daily requirements) should replace the ketogenic diet to support both glycemic control and weight management goals 7.
• Minimum 150 minutes per week of physical activity should be incorporated as part of comprehensive lifestyle management 6, 7.

Monitoring and Follow-Up

• Reassess HbA1c after 3 months to evaluate treatment effectiveness 8.
• Monitor for gastrointestinal adverse effects during GLP-1 receptor agonist titration, particularly nausea and vomiting 7.
• Continue monitoring renal function periodically, as metformin requires dose adjustment if eGFR falls below 45 mL/min/1.73m² 6.
• Educate the patient on recognizing early signs of ketoacidosis (nausea, vomiting, abdominal pain) and seeking immediate medical attention if these symptoms recur 1, 4.

Common Pitfalls to Avoid

• Never restart empagliflozin or any SGLT2 inhibitor in this patient, regardless of glycemic control, as EDKA represents an absolute contraindication 1, 2, 3, 4, 5.
• Do not delay GLP-1 receptor agonist initiation while attempting additional oral agents, as the HbA1c of 8.7% requires prompt intensification 6, 8.
• Avoid prescribing insulin as first-line intensification when the patient explicitly wants to avoid weight gain and GLP-1 receptor agonists offer superior weight outcomes 6, 7.
• Do not allow the patient to continue the ketogenic diet, as this significantly increases the risk of recurrent ketoacidosis even without SGLT2 inhibitor use 4.