What is the role of Sodium-Glucose Linked Transporter (SGLT) inhibitors, such as canagliflozin (canagliflozin) or dapagliflozin (dapagliflozin), in the management of type 1 diabetes?

SGLT Inhibitors in Type 1 Diabetes: Evidence and Recommendations

Direct Answer

SGLT inhibitors should generally NOT be used in type 1 diabetes due to a 5-17 times increased risk of diabetic ketoacidosis (DKA), with approximately 4% of treated patients developing this life-threatening complication. 1 The American Diabetes Association specifically warns against using SGLT inhibitors for treating type 1 diabetes due to this significant DKA risk. 1, 2

Regulatory Status and Approval

• No SGLT2 inhibitor has FDA approval for use in type 1 diabetes in the United States. 1
• Dapagliflozin is approved in the EU only for adults with T1D and BMI ≥27 kg/m² when insulin alone provides inadequate control, but this approval does not extend to the US. 3
• The FDA has issued specific warnings about the risk of euglycemic DKA with SGLT2 inhibitors in type 1 diabetes. 1, 2
• Dapagliflozin significantly increases the risk of diabetic ketoacidosis in patients with type 1 diabetes mellitus, a life-threatening event, beyond the background rate. 4

Clinical Trial Evidence

Efficacy Data

SGLT2 inhibitors demonstrate modest glycemic benefits in T1DM:

• Dapagliflozin 5 mg/day as adjunct to insulin improved HbA1c by approximately 0.4-0.5% over 24-52 weeks in the DEPICT-1 and -2 trials. 3, 5
• Total daily insulin dose reductions of approximately 8-20 units were observed. 3, 6
• Weight loss of 2-5 kg occurred with SGLT2 inhibitor use. 3, 6
• Hypoglycemia rates were generally similar to placebo. 3, 5

Sotagliflozin (Dual SGLT1/2 Inhibitor)

• Sotagliflozin showed similar modest benefits with A1C reductions and weight loss in clinical trials. 7, 8
• However, sotagliflozin use was associated with an eight-fold increase in DKA compared to placebo. 7, 8
• Sotagliflozin is not FDA-approved for glycemic management of type 1 diabetes in the United States. 8

The Critical Safety Concern: Diabetic Ketoacidosis

DKA Risk Magnitude

The risk of DKA is the primary reason SGLT inhibitors are contraindicated in T1DM:

• DKA risk increases 5-17 times in T1DM patients on SGLT inhibitors compared to those not on these medications. 1, 2
• Approximately 4% of people with type 1 diabetes treated with SGLT2 inhibitors develop DKA. 1
• In real-world practice, 12.8% of SGLT2i users experienced DKA over a mean duration of 29.5 months. 6
• Up to one-third of DKA cases present with glucose levels <200 mg/dL (euglycemic DKA), making detection more difficult. 2

Mechanisms of DKA with SGLT Inhibitors

Multiple pathways contribute to ketoacidosis risk: 7

• Increased ketone production due to reduction in insulin doses
• Increases in glucagon levels leading to increased lipolysis and ketone production
• Decreased renal clearance of ketones
• Urinary glucose excretion persists for 3 days after discontinuation, with some cases lasting up to 2 weeks 4

High-Risk Situations for DKA

Patients should avoid SGLT inhibitors during: 2, 4

• Illness or infection
• Reduced food intake or fasting
• Dehydration
• Alcohol consumption (especially binge drinking)
• Surgery or procedures with prolonged fasting
• Insulin pump malfunctions
• Significant reduction in insulin doses
• Ketogenic diets

Risk Mitigation Strategies (If Used Off-Label)

If SGLT inhibitors are considered despite recommendations against use, strict protocols are mandatory: 7

Patient Selection

• Assess underlying susceptibility to DKA before initiation 7
• Patients who have previously experienced DKA should NOT be treated with SGLT2 inhibitors under any circumstances 1
• Consider only in patients with BMI ≥27 kg/m² where DKA incidence may be lower 3, 9

Monitoring Requirements

• Prescribe home monitoring supplies for β-hydroxybutyrate 7
• Implement strict ketone monitoring protocols 1, 2
• Check for ketones in urine or blood even if blood glucose is <250 mg/dL 4

Patient Education

• Provide education regarding DKA risks, symptoms, and prevention strategies 7
• Instruct patients on signs and symptoms: nausea, vomiting, abdominal pain, tiredness, trouble breathing 4
• Patients must immediately stop SGLT inhibitors and seek medical attention if DKA symptoms develop 1, 2, 4

Ongoing Reassessment

• Reassessment of susceptibility, education, and provision of monitoring supplies should reoccur throughout treatment duration 7
• Withhold SGLT inhibitors at least 3 days prior to major surgery or procedures with prolonged fasting 4

Alternative Adjunctive Therapies for Type 1 Diabetes

Safer alternatives exist with lower DKA risk:

Pramlintide

• FDA-approved for use in adults with type 1 diabetes 7, 1, 2
• Modest A1C reductions of 0.3-0.4% 7
• Weight loss of approximately 1 kg 7
• No elevated DKA risk 1, 2

GLP-1 Receptor Agonists

• Show modest A1C reductions of 0.4% with liraglutide 1.8 mg daily 7
• Significant weight loss of approximately 5 kg 7
• Lower DKA risk compared to SGLT2 inhibitors 1, 2
• In real-world practice, only 3.9% of GLP-1RA users experienced DKA compared to 12.8% with SGLT2i 6
• Greater weight reduction compared to SGLT2i users (P = 0.027) with comparable HbA1c reduction 6

Real-World Evidence

A 2023 real-world study provides important safety data: 6

• After 1 year of GLP-1RA therapy: weight decreased from 90.5 kg to 85.4 kg, HbA1c from 7.7% to 7.3%, total daily insulin from 61.8 to 41.9 units
• After 1 year of SGLT2i therapy: HbA1c decreased from 7.9% to 7.3%, basal insulin from 31.3 to 25.6 units
• DKA occurred in 12.8% of SGLT2i users vs 3.9% of GLP-1RA users over mean duration of 29.5 months
• Therapy discontinuation due to adverse events: 26.9% for GLP-1RA vs 27.7% for SGLT2i

Clinical Decision Algorithm

When considering adjunctive therapy in T1DM:

1. First-line approach: Optimize insulin regimen and consider continuous glucose monitoring 8

2. If additional therapy needed:

   • Preferred option: Pramlintide (FDA-approved for T1DM) 1, 2
   • Alternative: GLP-1 receptor agonists (lower DKA risk than SGLT inhibitors) 1, 2, 6

3. SGLT inhibitors should be avoided due to unacceptable DKA risk that outweighs modest glycemic benefits 1, 8, 2

4. If SGLT inhibitors are used off-label despite recommendations:

   • Only in patients with BMI ≥27 kg/m² 3, 9
   • Never in patients with prior DKA history 1
   • Mandatory β-hydroxybutyrate monitoring supplies 7
   • Comprehensive DKA education program 9
   • Close follow-up with reassessment at each visit 7

Critical Pitfalls to Avoid

• Do not assume normal blood glucose excludes DKA - euglycemic DKA can occur with glucose <200 mg/dL 2, 4
• Do not continue SGLT inhibitors during illness, surgery, or reduced oral intake - these are high-risk situations for DKA 2, 4
• Do not use SGLT inhibitors in patients with any prior DKA episode - this is an absolute contraindication 1
• Do not rely solely on glucose monitoring - ketone monitoring is essential 7, 4

Bottom Line

The benefits of SGLT2 inhibitors in type 1 diabetes do not outweigh the significant risk of DKA in this population. 1, 8 While modest improvements in HbA1c, weight, and insulin requirements have been demonstrated in clinical trials, the 5-17 times increased risk of life-threatening DKA makes routine use inappropriate. 1, 2 Safer alternatives including pramlintide and GLP-1 receptor agonists should be prioritized when adjunctive therapy is needed. 1, 2, 6