In a type 2 diabetic patient with an A1c of 13.1% who is currently taking glipizide (a sulfonylurea) and premixed insulin, what is the next best medication regimen when a GLP‑1 receptor agonist is unavailable?

Next Best Medication Option When GLP-1 Receptor Agonist Is Unavailable

Add an SGLT2 inhibitor (empagliflozin 10 mg or dapagliflozin 10 mg daily) to the current regimen of glipizide and premixed insulin, while simultaneously optimizing metformin to at least 2000 mg daily if not already on it. 1

---

Rationale for SGLT2 Inhibitor as the Preferred Alternative

Cardiovascular and Renal Protection

• SGLT2 inhibitors provide proven cardiovascular and renal benefits independent of A1C level, making them the preferred second-line injectable-alternative agent when GLP-1 RAs are unavailable. 1, 2
• Empagliflozin, canagliflozin, and dapagliflozin each demonstrated statistically significant reductions in major adverse cardiovascular events (cardiovascular death, non-fatal MI, non-fatal stroke) in large randomized controlled trials. 2
• These agents reduce hospitalization for heart failure and slow progression of chronic kidney disease, benefits that are especially relevant in patients with severe hyperglycemia (A1C 13.1%). 1, 2

Glycemic Efficacy

• Adding an SGLT2 inhibitor to existing therapy lowers A1C by approximately 0.7–1.0%, which is meaningful but less than the 1–2% reduction typically seen with GLP-1 RAs. 1, 2
• In the context of an A1C of 13.1%, this reduction alone will not achieve target, but it provides a critical foundation for further intensification. 1

Complementary Mechanism with Insulin

• SGLT2 inhibitors work via an insulin-independent mechanism (renal glucose excretion), making them highly complementary to insulin therapy without increasing hypoglycemia risk when properly managed. 2, 3
• The combination of metformin, SGLT2 inhibitor, and insulin addresses multiple pathophysiologic defects in type 2 diabetes simultaneously. 3, 4

---

Immediate Medication Adjustments

1. Initiate SGLT2 Inhibitor

• Start empagliflozin 10 mg once daily or dapagliflozin 10 mg once daily in the morning with or without food. 2, 5
• Both agents are safe to initiate when eGFR ≥20 mL/min/1.73 m²; most patients with A1C 13.1% will meet this criterion unless advanced renal disease is present. 2

2. Reduce Insulin Dose by 10–20%

• When starting an SGLT2 inhibitor in a patient already receiving insulin, reduce the total daily insulin dose by approximately 10–20% to mitigate hypoglycemia risk. 2
• For example, if the patient is on 30 units of premixed insulin twice daily (60 units total), reduce to 24–27 units twice daily initially. 2

3. Optimize Metformin

• Metformin remains the preferred first-line agent and should be continued or titrated to at least 2000 mg daily (e.g., 1000 mg twice daily) unless contraindicated. 1, 2, 6
• Metformin reduces total insulin requirements by 20–30% and provides complementary glucose-lowering effects. 1
• In patients with eGFR ≥30 mL/min/1.73 m², metformin can be safely titrated up to 2000 mg daily. 2

4. Discontinue or Reduce Glipizide

• Sulfonylureas (glipizide) should be discontinued or reduced by 50% when intensifying insulin therapy to prevent additive hypoglycemia risk. 1
• Given the A1C of 13.1%, the sulfonylurea is clearly insufficient and adds primarily hypoglycemia risk rather than meaningful glycemic benefit. 1

---

Monitoring Protocol

First 2–3 Weeks After SGLT2 Inhibitor Initiation

• Check fasting glucose daily to guide insulin titration after the initial 10–20% reduction. 2
• If fasting glucose remains ≥180 mg/dL, increase basal insulin by 2–4 units every 3 days until fasting glucose reaches 80–130 mg/dL. 1, 2
• If fasting glucose falls <70 mg/dL, further reduce basal insulin by 10–20%. 1, 2

Ongoing Monitoring

• Re-assess A1C 3 months after starting the SGLT2 inhibitor; if A1C remains >8%, consider additional insulin intensification (e.g., transition from premixed to basal-bolus regimen) or addition of a GLP-1 receptor agonist if it becomes available. 2, 6
• Monitor for signs of diabetic ketoacidosis (DKA), especially if the patient becomes acutely ill, as SGLT2 inhibitors can cause euglycemic DKA. 4
• Check for genital mycotic infections, which occur more frequently with SGLT2 inhibitors. 3

---

Why Not Other Alternatives?

DPP-4 Inhibitors (e.g., Sitagliptin)

• DPP-4 inhibitors provide only modest A1C reduction (0.5–0.8%) and lack the cardiovascular and renal benefits of SGLT2 inhibitors. 6
• They are appropriate for patients with lower A1C levels (e.g., 7.5–8.5%) but insufficient for an A1C of 13.1%. 6

Thiazolidinediones (e.g., Pioglitazone)

• Pioglitazone is contraindicated in patients with heart failure history due to the risk of fluid retention, heart failure exacerbation, bone fractures, and weight gain. 6
• It also provides only modest A1C reduction (1–1.5%) and has a slow onset of action. 6

Further Insulin Intensification Alone

• Insulin intensification (e.g., transitioning from premixed to basal-bolus) is necessary but should not be the sole strategy when an A1C is 13.1%. 1
• Adding an SGLT2 inhibitor first provides cardiovascular and renal protection while reducing the total insulin dose required to achieve target. 1, 2
• The combination of SGLT2 inhibitor + insulin is superior to insulin alone in terms of weight, hypoglycemia risk, and cardiovascular outcomes. 2, 7

---

Expected Clinical Outcomes

Glycemic Control

• Adding an SGLT2 inhibitor is expected to lower A1C by 0.7–1.0%, moving a baseline A1C of 13.1% to approximately 12.1–12.4%. 2
• Subsequent insulin intensification (e.g., basal-bolus conversion) can provide an additional 1.5–2.0% A1C reduction, potentially achieving an A1C <10% within 3–6 months. 1, 2
• The combination of metformin, SGLT2 inhibitor, and optimized insulin can achieve an A1C reduction of 3–4% over 3–6 months, bringing the A1C closer to target. 1, 2

Cardiovascular and Renal Benefits

• SGLT2 inhibitor therapy reduces the risk of major adverse cardiovascular events and heart-failure hospitalization, translating into meaningful morbidity and mortality benefits. 1, 2
• These benefits are independent of A1C reduction and occur even in patients with severe hyperglycemia. 1, 2

---

Common Pitfalls to Avoid

Do Not Delay SGLT2 Inhibitor Initiation

• Do not wait for insulin optimization before starting an SGLT2 inhibitor; the cardiovascular and renal benefits begin immediately and are independent of glycemic control. 1, 2

Do Not Discontinue Metformin

• Never discontinue metformin when adding an SGLT2 inhibitor or intensifying insulin unless contraindicated, as this leads to higher insulin requirements and worse outcomes. 1, 2

Do Not Ignore Hypoglycemia Risk

• Failure to reduce insulin dose by 10–20% when starting an SGLT2 inhibitor is a common error that leads to preventable hypoglycemia. 2

Do Not Rely on Sliding-Scale Insulin

• Sliding-scale insulin as monotherapy is condemned by major diabetes guidelines and should never be the sole prandial strategy. 1
• Transitioning to a basal-bolus regimen (e.g., basal insulin + scheduled prandial insulin before each meal) markedly improves outcomes. 1

---

Alternative if SGLT2 Inhibitor Is Also Unavailable

Add a DPP-4 Inhibitor (Sitagliptin 100 mg Daily)

• If both GLP-1 RAs and SGLT2 inhibitors are unavailable, add sitagliptin 100 mg once daily to metformin and insulin. 6
• Sitagliptin provides a mean A1C reduction of approximately 0.5–0.8% with minimal hypoglycemia risk. 6
• However, this is a distant third choice because it lacks the cardiovascular and renal benefits of SGLT2 inhibitors and the superior glycemic efficacy of GLP-1 RAs. 6

---

Summary Algorithm

1. Start empagliflozin 10 mg or dapagliflozin 10 mg once daily. 2
2. Reduce total daily insulin dose by 10–20%. 2
3. Optimize metformin to at least 2000 mg daily. 1, 2
4. Discontinue or reduce glipizide by 50%. 1
5. Monitor fasting glucose daily for 2–3 weeks and titrate insulin as needed. 2
6. Re-assess A1C in 3 months; if >8%, consider basal-bolus insulin conversion or add GLP-1 RA if available. 2, 6