In an adult with type 1 diabetes, body‑mass index ≥ 27 kg/m², inadequate glycaemic control despite optimized basal‑bolus insulin therapy, and estimated glomerular filtration rate ≥ 45 mL/min/1.73 m², can a sodium‑glucose co‑transporter‑2 inhibitor (dapagliflozin or empagliflozin) be used off‑label?

Off-Label SGLT2 Inhibitor Use in Type 1 Diabetes

Direct Recommendation

Dapagliflozin 5 mg once daily can be used off-label as adjunct therapy to insulin in adults with type 1 diabetes who have BMI ≥ 27 kg/m², inadequate glycemic control despite optimized insulin therapy, and eGFR ≥ 45 mL/min/1.73 m², provided the patient receives comprehensive education about diabetic ketoacidosis risk mitigation and agrees to strict adherence to safety protocols. 1, 2

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Regulatory Context and Evidence Base

• Dapagliflozin is the only SGLT2 inhibitor that has been approved (temporarily in Europe, now withdrawn) specifically for type 1 diabetes, distinguishing it from empagliflozin which lacks this indication. 2, 3

• The European Medicines Agency initially approved dapagliflozin 5 mg daily as adjunct to insulin in adults with T1D and BMI ≥ 27 kg/m² when insulin alone provides inadequate control, though this recommendation was subsequently withdrawn due to safety concerns. 2, 3

• The FDA has not approved any SGLT2 inhibitor for type 1 diabetes, citing concerns about diabetic ketoacidosis risk. 3

• Both dapagliflozin and empagliflozin carry explicit FDA warnings that they are "not recommended for patients with type 1 diabetes." 4, 5

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Clinical Trial Evidence Supporting Efficacy

• In the DEPICT-1 and DEPICT-2 trials, dapagliflozin 5 mg daily as adjunct to insulin reduced HbA1c by approximately 0.4% compared to placebo over 24 weeks in adults with inadequately controlled T1D. 2, 6

• The subgroup of patients with BMI ≥ 27 kg/m² showed similar glycemic improvements and body weight reduction (approximately 3 kg) but importantly demonstrated less than half the diabetic ketoacidosis incidence compared to the overall trial population. 1, 2

• Dapagliflozin reduced total daily insulin dose by approximately 8-13% and increased time in target glucose range (70-180 mg/dL) without increasing severe hypoglycemia risk. 2, 6

• Real-world data with empagliflozin in 27 T1D patients showed HbA1c reduction from 8.0% to 7.2% at 52 weeks, with time in range increasing from 50% to 62%, alongside 8 kg weight loss and systolic blood pressure reduction from 134 to 127 mmHg. 7

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Critical Safety Considerations and DKA Risk

• Diabetic ketoacidosis is the most serious adverse event associated with SGLT2 inhibitors in type 1 diabetes, occurring more frequently than in placebo groups across all trials. 1, 6, 3

• The incidence of DKA in patients with BMI ≥ 27 kg/m² receiving dapagliflozin was less than half that of the overall trial population, making this BMI threshold clinically meaningful for patient selection. 1, 2

• Euglycemic DKA can occur with blood glucose levels below 250 mg/dL, making recognition challenging and delaying treatment initiation. 8, 1

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Mandatory Patient Education and Risk Mitigation Protocol

Before initiating off-label SGLT2 inhibitor therapy in type 1 diabetes, implement the following risk mitigation strategies:

• Educate patients to withhold dapagliflozin during any acute illness with reduced oral intake, fever, vomiting, or diarrhea, and stop at least 3 days before major surgery or procedures requiring prolonged fasting. 8, 9

• Instruct patients to maintain at least low-dose basal insulin even when dapagliflozin is held during illness, as complete insulin cessation dramatically increases DKA risk. 8, 9

• Teach patients to check blood or urine ketones if they develop malaise, nausea, vomiting, or abdominal pain—even when blood glucose is normal—and seek immediate medical attention if ketones are elevated. 8, 9

• Counsel patients about genital mycotic infections (occurring in approximately 6% vs 1% with placebo) and emphasize daily hygiene measures. 8, 9

• An independent DKA education program has been developed specifically for patients with T1D treated with SGLT inhibitors and should be utilized. 1

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Dosing Algorithm for Off-Label Use

Parameter	Recommendation	Citation
Starting dose	Dapagliflozin 5 mg once daily (do not use 10 mg dose approved for T2D)	[2,6]
Insulin adjustment	Reduce total daily insulin dose by 10-20% at initiation to prevent hypoglycemia	[2,6]
eGFR requirement	Must be ≥ 45 mL/min/1.73 m² for glycemic indication	[4]
BMI requirement	Must be ≥ 27 kg/m² (this threshold reduces DKA risk)	[1,2]
Monitoring frequency	Check ketones weekly for first month, then as clinically indicated	[1,3]

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Contraindications and Absolute Exclusions

• Do not use SGLT2 inhibitors in type 1 diabetes patients with eGFR < 45 mL/min/1.73 m², as the drug is likely ineffective for glycemic control based on mechanism of action. 4, 5

• Do not use in patients with history of recurrent diabetic ketoacidosis or those unable to reliably monitor ketones and recognize DKA symptoms. 1, 3

• Do not use in patients who cannot maintain adequate hydration or who have frequent episodes of acute illness. 8, 9

• Pregnancy and breastfeeding are absolute contraindications. 4, 5

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Why Empagliflozin Is Not Recommended for T1D

• Empagliflozin has never been approved for type 1 diabetes in any jurisdiction, unlike dapagliflozin which received temporary European approval. 2, 3

• The FDA label for empagliflozin explicitly states it "is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis." 5

• While real-world data with empagliflozin in T1D exists, the evidence base is substantially weaker than for dapagliflozin, which has dedicated phase III trials (DEPICT-1 and DEPICT-2) in this population. 2, 6, 7

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Common Pitfalls to Avoid

• Do not initiate SGLT2 inhibitors in type 1 diabetes without first optimizing basal-bolus insulin therapy and confirming inadequate control despite optimal insulin management. 1, 2

• Do not use the 10 mg dapagliflozin dose approved for type 2 diabetes; the 5 mg dose is specifically studied and recommended for type 1 diabetes. 2, 6

• Do not discontinue basal insulin when adding dapagliflozin, as this dramatically increases DKA risk even with normal blood glucose levels. 8, 1

• Do not assume normal blood glucose excludes diabetic ketoacidosis; euglycemic DKA is a hallmark complication of SGLT2 inhibitors in type 1 diabetes. 8, 1, 3

• Do not use SGLT2 inhibitors in type 1 diabetes patients who cannot commit to rigorous ketone monitoring and sick-day management protocols. 1, 3

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Clinical Decision Framework

Proceed with off-label dapagliflozin 5 mg daily if ALL of the following criteria are met:

1. Adult patient with confirmed type 1 diabetes
2. BMI ≥ 27 kg/m²
3. eGFR ≥ 45 mL/min/1.73 m²
4. HbA1c remains elevated despite optimized basal-bolus insulin therapy
5. Patient demonstrates reliable adherence to insulin therapy
6. Patient can perform ketone monitoring and recognizes DKA symptoms
7. Patient agrees to strict sick-day rules and withholding protocols
8. No history of recurrent diabetic ketoacidosis
9. Shared decision-making discussion documenting understanding of off-label use and DKA risk

1, 2, 6, 3