SGLT-2 Inhibitors as Second-Line Therapy After Metformin in Type 2 Diabetes
Add an SGLT-2 inhibitor (empagliflozin, canagliflozin, or dapagliflozin) to metformin for patients with type 2 diabetes not achieving glycemic targets, as this combination provides superior cardiovascular, renal, and mortality benefits compared to other second-line options. 1
Primary Recommendation: SGLT-2 Inhibitors
KDIGO 2020 guidelines strongly recommend treating patients with T2D and eGFR ≥30 ml/min per 1.73 m² with an SGLT-2 inhibitor (Grade 1A recommendation), making this the highest-level evidence-based recommendation for second-line therapy. 1
Key Clinical Benefits Beyond Glycemic Control
SGLT-2 inhibitors reduce cardiovascular death by 38% (HR 0.62,95% CI 0.49-0.77), as demonstrated in the EMPA-REG OUTCOME trial with empagliflozin. 2
These agents provide documented kidney protection, reducing progression of chronic kidney disease and albuminuria, independent of their glucose-lowering effects. 1
SGLT-2 inhibitors reduce heart failure hospitalizations and provide blood pressure reduction (typically 3-5 mmHg systolic), offering multiple cardiometabolic benefits. 1, 3
Weight loss of 2-3 kg occurs consistently with SGLT-2 inhibitors, contrasting with the weight gain seen with sulfonylureas. 4, 3
Specific SGLT-2 Inhibitor Selection
The 2022 KDIGO/ADA consensus recommends prioritizing agents with documented cardiovascular and kidney benefits, specifically empagliflozin, canagliflozin, or dapagliflozin. 1
Dosing Strategy
Start empagliflozin at 10 mg once daily with no titration required for cardiovascular risk reduction, though the dose may be increased to 25 mg for additional glycemic benefit. 1, 2
Start canagliflozin at 100 mg once daily or dapagliflozin at 10 mg once daily, with similar principles regarding cardiovascular benefits at the lowest dose. 1
No dose titration is necessary for cardiovascular or renal protection—the benefits occur at the starting dose. 1
When to Add SGLT-2 Inhibitors
SGLT-2 inhibitors should be added even if glycemic targets are already met with metformin alone, given their cardiovascular and renal benefits are independent of glucose lowering. 1
Specific Clinical Scenarios Favoring SGLT-2 Inhibitors
Patients with established atherosclerotic cardiovascular disease (prior MI, stroke, coronary revascularization, or peripheral artery disease) should receive an SGLT-2 inhibitor regardless of current HbA1c. 1
Patients with heart failure (reduced or preserved ejection fraction) benefit particularly from SGLT-2 inhibitors due to proven reduction in heart failure hospitalizations. 1
Patients with chronic kidney disease (eGFR 20-90 ml/min per 1.73 m² and/or albuminuria) should receive SGLT-2 inhibitors for renal protection. 1
Patients requiring weight loss or blood pressure reduction gain additional benefits from SGLT-2 inhibitors compared to other second-line agents. 3
Medication Adjustments When Adding SGLT-2 Inhibitors
For patients on insulin or sulfonylureas who are meeting glycemic targets, reduce or discontinue the sulfonylurea or reduce insulin dose by 10-20% before adding an SGLT-2 inhibitor to prevent hypoglycemia. 1
- Metformin should be continued when adding an SGLT-2 inhibitor unless contraindicated by renal function (eGFR <30 ml/min per 1.73 m²). 1
Critical Safety Considerations and Risk Mitigation
Volume Depletion Management
Before starting an SGLT-2 inhibitor, consider reducing thiazide or loop diuretic doses in patients at risk for hypovolemia, and counsel patients about symptoms of volume depletion. 1
Ketoacidosis Prevention
Withhold SGLT-2 inhibitors during prolonged fasting, surgery, or critical medical illness when patients are at greater risk for ketosis, even though diabetic ketoacidosis risk is low. 1, 3
- Instruct patients to discontinue SGLT-2 inhibitors and seek immediate medical attention if symptoms of ketoacidosis occur (nausea, vomiting, abdominal pain, labored breathing), even with normal blood glucose. 2
Genital Mycotic Infections
Female genital mycotic infections occur in approximately 10-15% of women and male genital infections (balanitis) in 3-5% of men taking SGLT-2 inhibitors. 5, 3
- Counsel patients about these infections before starting therapy and provide information on recognition and treatment options. 2
Urinary Tract Infections
Urinary tract infections occur more frequently with SGLT-2 inhibitors (7-9% vs 5-6% with placebo), and patients should be advised to seek medical attention for symptoms. 2, 5
Renal Function Monitoring
A reversible decrease in eGFR of 3-5 ml/min per 1.73 m² commonly occurs within the first 4 weeks of SGLT-2 inhibitor initiation and is generally not an indication to discontinue therapy. 1
- Once initiated, continue SGLT-2 inhibitors even if eGFR falls below 30 ml/min per 1.73 m² (or below 20 ml/min per 1.73 m² per updated 2022 guidelines), unless not tolerated or dialysis is initiated. 1
Alternative Second-Line Options When SGLT-2 Inhibitors Are Contraindicated
If SGLT-2 inhibitors are contraindicated or not tolerated, add a GLP-1 receptor agonist (liraglutide, dulaglutide, or semaglutide) as these agents also provide proven cardiovascular benefits. 6, 7
GLP-1 Receptor Agonists as Alternative
GLP-1 receptor agonists reduce major adverse cardiovascular events (MI, stroke, cardiovascular death) in patients with established ASCVD or high cardiovascular risk. 1, 6
Start liraglutide at 0.6 mg subcutaneously daily and titrate to 1.8 mg daily, or start dulaglutide at 0.75 mg weekly and titrate to 1.5 mg weekly, or start semaglutide at 0.25 mg weekly and titrate to 1 mg weekly. 6
GLP-1 receptor agonists can be used in advanced CKD (eGFR <20 ml/min per 1.73 m²) where SGLT-2 inhibitors have diminished efficacy. 7
What NOT to Use as Second-Line Therapy
Avoid sulfonylureas (glimepiride, glipizide, glyburide) when SGLT-2 inhibitors or GLP-1 receptor agonists are available, as sulfonylureas cause significant hypoglycemia (24% vs 2% with empagliflozin), weight gain, and lack cardiovascular benefits. 6, 4
- Do not add another DPP-4 inhibitor if the patient is already on one, as combining two drugs from the same class provides no benefit. 6
Contraindications to SGLT-2 Inhibitor Initiation
Do not initiate SGLT-2 inhibitors in patients with eGFR <20 ml/min per 1.73 m² (updated from <30 ml/min per 1.73 m² in 2020), during pregnancy or breastfeeding, or in patients under 18 years of age. 1, 2
- SGLT-2 inhibitors have not been adequately studied in kidney transplant recipients who may be at increased risk for infections due to immunosuppression. 1