What are the considerations for using Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors, such as canagliflozin (canagliflozin) or empagliflozin (empagliflozin), in a patient with type 2 diabetes (T2D) who has undergone a renal transplant and has a history of chronic kidney disease (CKD) and is on immunosuppression?

SGLT2 Inhibitors in Renal Transplant Recipients with Type 2 Diabetes

Primary Recommendation

SGLT2 inhibitors are NOT recommended for routine use in kidney transplant recipients with type 2 diabetes, as they have not been adequately studied in this immunosuppressed population and the standard recommendation does not apply to transplant patients. 1

Guideline Position on Transplant Recipients

The most recent KDIGO 2022 guidelines explicitly state that SGLT2 inhibitors have not been adequately studied in kidney transplant recipients and therefore the recommendation to use SGLT2 inhibitors does not apply to this population. 1 This represents a clear exclusion from the otherwise strong 1A recommendation for SGLT2 inhibitor use in patients with type 2 diabetes and CKD with eGFR ≥20 mL/min/1.73 m². 1

Rationale for Guideline Exclusion

The guidelines acknowledge that transplant recipients:

• May theoretically benefit from SGLT2 inhibitor treatment 1
• Are immunosuppressed and potentially at increased risk for infections 1
• Have not been included in major cardiovascular and renal outcome trials 1, 2

Alternative Treatment Approach

For glycemic control in kidney transplant recipients with type 2 diabetes, prioritize:

First-Line Therapy

• Metformin if eGFR >30 mL/min/1.73 m² (reduce dose to 1000 mg/day if eGFR 30-44 mL/min/1.73 m²) 1

Second-Line Therapy

• GLP-1 receptor agonists (liraglutide, semaglutide, or dulaglutide) for patients not meeting glycemic targets, as these provide cardiovascular benefits with no dose adjustment required for most agents 1
• Dulaglutide can be used with eGFR >15 mL/min/1.73 m² 1

Additional Considerations

• ACE inhibitors or ARBs remain first-line for renal protection if albuminuria is present 1
• Avoid sulfonylureas when possible due to hypoglycemia risk, particularly glyburide which should never be used in CKD 1

Emerging Research Evidence (Not Yet Guideline-Supported)

While guidelines exclude transplant recipients, small observational studies suggest potential feasibility:

Limited Case Series Data

• A 10-patient case series using empagliflozin showed stable allograft function over 12 months with median eGFR 57 mL/min/1.73 m² at baseline 3
• HbA1c decreased modestly from 7.3% to 7.1% 3
• Low rate of urinary tract infections and other side effects 3

Systematic Review Findings

• A review of 9 studies (144 patients total) showed stable renal allograft function, modest glycemic improvement, weight reduction, and low incidence of reversible adverse effects 2
• Larger HbA1c reductions (-0.5 to 1.5% points) only seen in patients with eGFR >60 mL/min/1.73 m² and HbA1c >8% 4

Critical Caveats and Contraindications

Absolute Contraindications

• Severe renal impairment, ESRD, or dialysis (FDA contraindication for empagliflozin) 5
• History of serious hypersensitivity to SGLT2 inhibitors 5

Specific Transplant-Related Concerns

• Infection risk: Immunosuppression may amplify the known risk of genital mycotic infections (6% vs 1% placebo in non-transplant trials) 1
• Volume depletion: Particularly concerning with concurrent calcineurin inhibitor use and baseline tenuous volume status 1
• Drug interactions: Potential interactions with immunosuppressive agents have not been systematically studied 3

When to Withhold (If Ever Used Off-Label)

• During prolonged fasting, surgery, or critical medical illness (increased ketosis risk) 1, 6
• Acute illness with fluid losses 6
• History of recurrent urinary tract infections 3

Monitoring Requirements (If Used Off-Label)

If SGLT2 inhibitors are considered in highly selected transplant recipients despite guideline exclusion:

• Baseline requirements: Stable allograft function, no history of recurrent UTIs 3
• eGFR monitoring: Within 2-4 weeks after initiation, then every 3-6 months 1
• Volume status assessment: Follow up after drug initiation for symptoms of depletion 1
• Infection surveillance: Educate on genital hygiene and symptoms of mycotic infections 1
• Ketone monitoring: Blood or urine ketones during acute illness, especially if on insulin 1

Clinical Decision Algorithm

For a kidney transplant recipient with T2D requiring additional glucose control:

1. Optimize metformin (if eGFR permits) 1
2. Add GLP-1 receptor agonist with documented cardiovascular benefits 1
3. Consider insulin if further glycemic control needed 1
4. Do NOT routinely add SGLT2 inhibitor per current guidelines 1
5. If considering SGLT2 inhibitor off-label: Only in highly selected patients with stable allograft function (eGFR >45-60 mL/min/1.73 m²), no recurrent infections, adequate volume status, and after shared decision-making about lack of safety data in this population 3, 2, 4