Discontinue Glyburide and Uptitrate Tirzepatide
The most appropriate next step is to discontinue glyburide immediately and increase tirzepatide from 5 mg to 10 mg weekly, while continuing empagliflozin 25 mg daily. This patient's HbA1c of 8.2% indicates inadequate glycemic control despite triple therapy, and the current regimen includes a high-risk sulfonylurea that provides no cardiovascular or renal protection in a patient with stage 3a chronic kidney disease (eGFR 78 mL/min/1.73 m²).
Rationale for Stopping Glyburide
Glyburide is contraindicated in patients with any degree of renal impairment because its active metabolites accumulate and cause prolonged, severe hypoglycemia—a risk that increases as kidney function declines 1.
Sulfonylureas provide zero cardiovascular or renal protection and actually increase hypoglycemia risk, especially when combined with other glucose-lowering agents 1, 2.
The 2020 ACC/AHA consensus explicitly recommends discontinuing sulfonylureas when initiating or uptitrating GLP-1 receptor agonists or SGLT2 inhibitors to prevent hypoglycemia without sacrificing cardiovascular benefit 1.
Combining glyburide with tirzepatide raises hypoglycemia risk without adding cardiovascular benefit; the sulfonylurea should be stopped completely when the GLP-1 receptor agonist is uptitrated 1.
Tirzepatide Dose Escalation
Tirzepatide should be increased from 5 mg to 10 mg weekly because the current dose has not achieved the HbA1c target after an appropriate trial period (typically 3 months) 1, 3.
The SURPASS clinical trial program demonstrated that tirzepatide 10 mg weekly reduces HbA1c by 2.0–2.3% from baseline levels of 8.0–8.5%, making it highly effective for patients with HbA1c 8.2% 3, 4.
Tirzepatide 10 mg weekly produces superior HbA1c reduction compared with semaglutide 1.0 mg weekly and basal insulin, with 40–50% of patients achieving HbA1c <5.7% (normoglycemia) 3, 4.
The dose can be further increased to 15 mg weekly if HbA1c remains >7.0% after 4 weeks on the 10 mg dose, as the highest dose provides an additional 0.3–0.5% HbA1c reduction 3, 4.
Continue Empagliflozin for Cardiorenal Protection
Empagliflozin 25 mg daily should be continued unchanged because it provides robust cardiovascular and renal protection independent of glycemic control 1.
SGLT2 inhibitors reduce major adverse cardiovascular events, heart failure hospitalization, and chronic kidney disease progression across the spectrum of baseline HbA1c, including patients already at glycemic target 1.
The decision to use empagliflozin for cardiovascular and renal protection should be made independently of baseline HbA1c or individualized HbA1c target, as the benefits are not restricted to patients with elevated HbA1c 1.
At eGFR 78 mL/min/1.73 m², empagliflozin retains full glucose-lowering efficacy and provides maximum cardiorenal benefit without requiring dose adjustment 1.
Expected Glycemic Outcomes
The combination of tirzepatide 10 mg weekly plus empagliflozin 25 mg daily should reduce HbA1c from 8.2% to approximately 6.0–6.5% based on the additive effects of these agents 3, 4.
Tirzepatide alone at 10 mg weekly reduces HbA1c by 2.0–2.3% from baseline, and empagliflozin contributes an additional 0.6–0.8% reduction when used in combination 3, 5, 6.
This regimen will also produce substantial weight loss (8–12 kg) and modest blood pressure reduction (3–5 mmHg systolic), both of which improve cardiovascular risk 3, 5, 4.
Monitoring and Safety
Reassess HbA1c in 3 months to determine whether the 10 mg dose is sufficient or whether uptitration to 15 mg weekly is needed 1, 3.
Monitor for gastrointestinal adverse effects (nausea, vomiting, diarrhea) during the first 4–8 weeks after dose escalation; these symptoms are usually transient and can be mitigated by eating smaller meals 1, 4.
Check eGFR and electrolytes 1–2 weeks after stopping glyburide to ensure renal function remains stable, as empagliflozin may cause a reversible 2–5 mL/min/1.73 m² eGFR dip 1.
Educate the patient to withhold empagliflozin during acute illness (fever, vomiting, diarrhea, reduced oral intake) and to stop it at least 3 days before major surgery to prevent euglycemic diabetic ketoacidosis 1.
Counsel about genital mycotic infections (6% incidence with SGLT2 inhibitors) and emphasize daily hygiene 1.
Common Pitfalls to Avoid
Do not continue glyburide "just to see" if the combination works—the sulfonylurea adds hypoglycemia risk without cardiovascular benefit and is inappropriate in CKD 1.
Do not reduce empagliflozin dose when eGFR is 78 mL/min/1.73 m²—the full 25 mg dose is appropriate and provides maximum cardiorenal protection 1.
Do not delay tirzepatide uptitration beyond 4 weeks if HbA1c remains elevated—the drug has a rapid onset of action and dose escalation should proceed according to the manufacturer's schedule 3, 4.
Do not stop empagliflozin if eGFR falls below 45 mL/min/1.73 m²—cardiovascular and renal benefits persist even when glucose-lowering efficacy diminishes 1.