What are the considerations for using Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors for kids with type 2 diabetes?

SGLT2 Inhibitors for Pediatric Type 2 Diabetes

Empagliflozin is now FDA-approved and recommended for children aged 10 years and older with type 2 diabetes, demonstrating significant A1C reduction (0.84%) without severe hypoglycemia, while canagliflozin is also approved for this age group. 1, 2

Current FDA-Approved Options for Youth

Two SGLT2 inhibitors are currently approved for pediatric use:

• Empagliflozin: Approved for children aged 10-17 years with type 2 diabetes, with dosing starting at 10 mg daily and potential escalation to 25 mg if A1C remains ≥7.0% after 12 weeks 1
• Canagliflozin: FDA-approved for patients aged 10 years and older with type 2 diabetes as an adjunct to diet and exercise 2

When to Use SGLT2 Inhibitors in Pediatric Patients

SGLT2 inhibitors should be added when metformin alone fails to achieve glycemic targets (A1C <7%) in youth with type 2 diabetes. 1

Treatment Algorithm:

First-line therapy:

• Metformin remains the initial medication for metabolically stable youth (A1C <8.5% without ketosis), titrated to 2,000 mg daily 1

Add SGLT2 inhibitor when:

• A1C goals are not met on metformin monotherapy 1
• Patient requires additional glucose-lowering beyond metformin 1
• GLP-1 receptor agonists are not tolerated or contraindicated 1

Do NOT use SGLT2 inhibitors when:

• Patient presents with diabetic ketoacidosis or marked ketosis (use insulin first) 1
• eGFR <30 mL/min/1.73 m² for glycemic control 2
• Patient has type 1 diabetes 2

Efficacy Data in Youth

Meta-analysis of pediatric trials demonstrates:

• Mean A1C reduction of 0.93% compared to placebo (95% CI: -1.36 to -0.49) 3
• 36% lower risk of requiring rescue medication or discontinuation due to lack of efficacy (RR=0.64) 3
• Consistent glucose-lowering maintained across 37.79 weeks of follow-up 3

The empagliflozin pediatric trial specifically showed:

• Significant A1C reduction of 0.84% in the pooled empagliflozin group versus placebo (p=0.012) 1
• Zero episodes of severe hypoglycemia during the study period 1

Safety Profile in Pediatric Populations

SGLT2 inhibitors demonstrate comparable safety to placebo in youth:

• No significant difference in overall adverse events (RR=1.10,95% CI: 0.96-1.27) 3
• No significant difference in serious adverse events (RR=1.06,95% CI: 0.44-2.57) 3
• Most common side effect is genital mycotic infections, which are mild to moderate and easily treatable 1, 3, 4

Critical Safety Warnings:

Diabetic ketoacidosis risk:

• Monitor for ketoacidosis regardless of blood glucose levels, especially in patients with insulin deficiency 1
• Withhold SGLT2 inhibitors at least 3 days before surgery or procedures with prolonged fasting 2
• Educate patients on sick-day management and when to hold medication 1

Volume depletion concerns:

• Assess volume status before initiating, particularly in patients on diuretics or ACE inhibitors 1, 2
• Monitor for orthostatic hypotension and dehydration 1

Urinary tract infections:

• Evaluate and treat promptly if signs of urosepsis or pyelonephritis develop 2
• Risk of urinary tract infections is not significantly elevated in pediatric trials 3

Canagliflozin-specific concerns:

• Increased amputation risk (HR 1.97) and fracture risk (HR 1.26) observed in adult trials 1
• Uncertain if these are class effects, but warrants monitoring in youth on canagliflozin 1

Renal Function Considerations

SGLT2 inhibitors require adequate renal function for glucose-lowering efficacy:

• Full efficacy expected with eGFR ≥45 mL/min/1.73 m² 5
• Substantially reduced glucose-lowering with eGFR 30-45 mL/min/1.73 m² 5
• Minimal to no glucose-lowering effect with eGFR <30 mL/min/1.73 m² 5
• Not recommended for glycemic control when eGFR <30 mL/min/1.73 m² 2

Monitor renal function:

• Assess before initiating therapy 2
• Monitor as clinically indicated, particularly during acute illness 2

Practical Implementation

Dosing for empagliflozin in youth aged 10-17 years:

• Start 10 mg once daily before first meal 1
• If A1C remains ≥7.0% at week 12, increase to 25 mg daily 1

Dosing for canagliflozin in patients aged ≥10 years:

• Start 100 mg once daily before first meal 2
• Can increase to 300 mg daily in patients tolerating 100 mg who have eGFR ≥60 mL/min/1.73 m² and require additional glycemic control 2

Monitoring requirements:

• Blood glucose monitoring plans should be individualized based on pharmacologic regimen 1
• Consider continuous glucose monitoring (CGM) for patients requiring frequent monitoring, though data in youth with type 2 diabetes are limited 1
• Measure A1C at least every 3 months 6

Common Pitfalls to Avoid

Do not discontinue SGLT2 inhibitors solely because glucose-lowering efficacy has declined with reduced eGFR - cardiovascular and renal benefits persist even when glycemic effects are minimal 5

Do not use SGLT2 inhibitors as monotherapy in patients presenting with random glucose ≥250 mg/dL or A1C ≥8.5% - these patients require insulin initially 1

Do not forget to reduce insulin or sulfonylurea doses when adding SGLT2 inhibitors - this combination increases hypoglycemia risk 1, 2

Do not continue SGLT2 inhibitors during acute illness, severe dehydration, or prolonged fasting - hold medication to prevent ketoacidosis and volume depletion 1, 2