What is the preferred addition to metformin for treating type 2 diabetes mellitus, an SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitor or a DPP4 (Dipeptidyl Peptidase-4) inhibitor?

SGLT2 Inhibitors Over DPP-4 Inhibitors as Second-Line Therapy

Add an SGLT2 inhibitor, not a DPP-4 inhibitor, to metformin for treating type 2 diabetes when glycemic targets are not met. 1

Primary Recommendation

The American College of Physicians (2024) provides a strong recommendation with high-certainty evidence to add an SGLT2 inhibitor to metformin and lifestyle modifications, while explicitly recommending against adding a DPP-4 inhibitor to reduce morbidity and all-cause mortality. 1 This represents the most recent and definitive guidance prioritizing patient-centered outcomes.

Evidence Supporting SGLT2 Inhibitors

SGLT2 inhibitors provide mortality and cardiovascular benefits that DPP-4 inhibitors do not:

• SGLT2 inhibitors reduce all-cause mortality, major adverse cardiovascular events (MACE), progression of chronic kidney disease, and hospitalization for heart failure. 1
• Empagliflozin reduced cardiovascular death by 38% (HR 0.62) and all-cause mortality by 32% (HR 0.68) in patients with established cardiovascular disease. 1
• Canagliflozin reduced the composite renal endpoint by 30% (HR 0.70) and hospitalization for heart failure by 39% (HR 0.61) in patients with diabetic kidney disease. 1
• Dapagliflozin reduced cardiovascular death or heart failure hospitalization by 25% (HR 0.75) even in patients without diabetes but with heart failure. 1

DPP-4 inhibitors lack these critical benefits:

• The ACP guideline explicitly states DPP-4 inhibitors should not be added to metformin because they do not reduce morbidity or all-cause mortality. 1
• DPP-4 inhibitors are relegated to a lower tier in treatment algorithms, listed after GLP-1 receptor agonists and only when other options are unsuitable. 1

Treatment Algorithm

First-line therapy for all patients with type 2 diabetes and eGFR ≥30 mL/min/1.73 m²:

• Metformin PLUS an SGLT2 inhibitor together as initial combination therapy. 1

If additional glycemic control is needed beyond metformin + SGLT2 inhibitor:

• Add a GLP-1 receptor agonist (preferred third agent). 1
• Consider DPP-4 inhibitors only if GLP-1 receptor agonists are not tolerated or contraindicated. 1

Prioritize SGLT2 inhibitors specifically in patients with:

• Chronic kidney disease (eGFR 30-60 mL/min/1.73 m²). 1
• Established heart failure or high risk for heart failure. 1
• Established atherosclerotic cardiovascular disease. 1
• Need for weight loss and blood pressure reduction. 1, 2

Practical Considerations

SGLT2 inhibitor selection and dosing:

• Canagliflozin: 100 mg once daily before first meal, may increase to 300 mg. 3
• Empagliflozin: 10 mg or 25 mg once daily. 1
• Dapagliflozin: 10 mg once daily. 1
• All can be continued even if eGFR falls below initiation thresholds, unless not tolerated. 1

Common pitfalls to avoid:

• Counsel patients about genital mycotic infections (increased risk with SGLT2 inhibitors) and proper genital hygiene. 1, 2
• Educate about diabetic ketoacidosis risk and its signs/symptoms, particularly during illness or fasting. 1, 2
• Monitor for volume depletion and consider reducing diuretic doses in high-risk patients. 4
• Do not use DPP-4 inhibitors as second-line therapy when SGLT2 inhibitors are available and appropriate. 1

When DPP-4 inhibitors might be considered:

• Frail elderly patients where side effects are a major concern. 2
• eGFR <30 mL/min/1.73 m² where SGLT2 inhibitors cannot be initiated. 1
• Patients with recurrent genital infections or other contraindications to SGLT2 inhibitors. 2
• Cost constraints where SGLT2 inhibitors are prohibitively expensive and cardiovascular/renal disease is absent. 1

Strength of Evidence

The 2024 ACP guideline represents the highest quality and most recent evidence, providing a strong recommendation based on high-certainty evidence for SGLT2 inhibitors and explicitly recommending against DPP-4 inhibitors. 1 This is reinforced by the 2022 KDIGO guidelines recommending both metformin and SGLT2 inhibitors as first-line therapy together. 1 Multiple cardiovascular outcomes trials (EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, CREDENCE) demonstrate consistent mortality and cardiovascular benefits with SGLT2 inhibitors that are absent in DPP-4 inhibitor trials. 1