Why are SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors approved for type 2 diabetes but discouraged in type 1 diabetes despite increasing the risk of Diabetic Ketoacidosis (DKA) in both?

SGLT2 Inhibitors in Type 1 vs Type 2 Diabetes: DKA Risk Considerations

SGLT2 inhibitors are approved for type 2 diabetes but contraindicated in type 1 diabetes because the risk of diabetic ketoacidosis (DKA) is significantly higher and more dangerous in type 1 diabetes due to absolute insulin deficiency, despite both populations experiencing increased DKA risk with these medications. 1, 2

Mechanism of DKA Risk with SGLT2 Inhibitors

• SGLT2 inhibitors work by blocking glucose reabsorption in the proximal renal tubules, increasing urinary glucose excretion and lowering blood glucose levels independent of insulin action 3
• These medications can increase ketone body production through several mechanisms:
  • Reduced insulin levels and increased glucagon secretion, shifting metabolism toward fat oxidation 4
  • Increased renal glucose excretion leading to a relative state of carbohydrate deprivation 5
  • Volume depletion that can trigger stress hormone release 1

Different Risk Profiles Between Type 1 and Type 2 Diabetes

Type 1 Diabetes (Contraindicated)

• Patients with type 1 diabetes have absolute insulin deficiency, making them inherently more susceptible to ketosis 1
• Clinical trials showed markedly increased risk of ketoacidosis in type 1 diabetes patients receiving SGLT2 inhibitors compared to placebo 6
• FDA explicitly states: "SGLT2 inhibitors are not indicated for glycemic control in patients with type 1 diabetes mellitus" 1, 2
• The risk of euglycemic DKA (ketoacidosis with normal or only slightly elevated blood glucose) is particularly concerning in type 1 diabetes, as it may delay diagnosis and treatment 5

Type 2 Diabetes (Approved)

• Patients with type 2 diabetes typically retain some endogenous insulin production, providing some protection against ketosis 3
• The risk-benefit profile is more favorable in type 2 diabetes due to:
  • Lower baseline risk of DKA compared to type 1 diabetes 4
  • Significant cardiovascular and renal benefits that outweigh the DKA risk 6
  • SGLT2 inhibitors reduce the risk of heart failure hospitalizations, cardiovascular death, and slow CKD progression in type 2 diabetes 6

Clinical Benefits in Type 2 Diabetes That Justify Use Despite DKA Risk

• SGLT2 inhibitors provide multiple benefits in type 2 diabetes beyond glycemic control:
  • Reduced risk of major adverse cardiovascular events 6
  • Slowed progression of chronic kidney disease with demonstrated benefits at eGFR levels as low as 20 mL/min/1.73m² 6
  • Reduced hospitalization for heart failure in patients with both reduced and preserved ejection fraction 6
  • Weight reduction and blood pressure lowering effects 7

Preventive Strategies for DKA in Type 2 Diabetes

• Temporary discontinuation of SGLT2 inhibitors during high-risk situations:
  • Major surgery or procedures requiring fasting 1
  • Acute illness or infection 1
  • Extreme reduction in carbohydrate intake or ketogenic diets 8
• Patient education about signs and symptoms of DKA, including nausea, vomiting, abdominal pain, fatigue, and shortness of breath 1
• Consider ketone monitoring in high-risk patients (those with pancreatic disorders or low insulin secretory capacity) 1
• Avoid excessive alcohol consumption while taking SGLT2 inhibitors 5

Conclusion

The differential approval status of SGLT2 inhibitors between type 1 and type 2 diabetes reflects a careful risk-benefit assessment. While the DKA risk exists in both populations, the absolute risk is significantly higher in type 1 diabetes due to complete insulin deficiency, and the potential benefits don't outweigh this risk. In contrast, for type 2 diabetes, the cardiovascular and renal protective effects provide substantial benefits that justify their use with appropriate precautions to minimize DKA risk 6, 1.