Are any SGLT2 (sodium-glucose cotransporter 2) inhibitors safer in patients with type 1 diabetes mellitus (T1DM)?

No SGLT2 Inhibitor is Safe for Type 1 Diabetes Mellitus

SGLT2 inhibitors are not recommended for use in type 1 diabetes due to the significantly increased risk of diabetic ketoacidosis (DKA), with no single agent demonstrating a superior safety profile in this population. 1, 2

Risk of Diabetic Ketoacidosis with SGLT2 Inhibitors in T1DM

• SGLT2 inhibitors increase the risk of DKA 5-17 times higher in patients with type 1 diabetes compared to those not on these medications 2
• Approximately 4% of people with type 1 diabetes treated with SGLT2 inhibitors develop DKA 2
• The American Diabetes Association specifically warns against using SGLT inhibitors (including SGLT-1, SGLT-2, and dual SGLT-1/2 inhibitors) for treating type 1 diabetes due to this significant DKA risk 1, 3
• The FDA has issued specific warnings about the risk of euglycemic DKA with SGLT2 inhibitors in type 1 diabetes 2

Comparative Safety Among SGLT2 Inhibitors

• Recent network meta-analysis data shows that dapagliflozin 5mg (OR: 2.57), empagliflozin 10mg (OR: 2.68), sotagliflozin 200mg (OR: 4.04), and sotagliflozin 400mg (OR: 5.96) all demonstrated significantly higher DKA risk compared to placebo 4
• While some data suggests canagliflozin 300mg might have a lower incidence of DKA compared to other SGLT2 inhibitors, all agents in this class carry substantial risk when used in type 1 diabetes 4
• No SGLT2 inhibitor has FDA approval for use in type 1 diabetes in the United States 2

Unique Challenges with DKA in SGLT2 Inhibitor Use

• Euglycemic DKA can occur with normal or only slightly elevated blood glucose levels (<200 mg/dL), making detection more difficult 2
• Risk factors that increase DKA likelihood in T1DM patients on SGLT2 inhibitors include:
  • Very low-carbohydrate diets and prolonged fasting 2
  • Excessive alcohol intake 2
  • Volume depletion and dehydration 2
  • Reduced insulin dosing 5
  • Illness or infection 1

Alternative Adjunctive Therapies for Type 1 Diabetes

• Pramlintide is FDA-approved for use in adults with type 1 diabetes, offering modest A1C reductions (0-0.3%) and weight benefits (1-2 kg) without the elevated DKA risk 1
• GLP-1 receptor agonists show modest A1C reductions (0.2-0.5%) with significant weight loss benefits (approximately 3 kg) and lower DKA risk compared to SGLT2 inhibitors 1
• Clinical trials with liraglutide 1.8 mg daily in type 1 diabetes have shown modest A1C reductions (0.4%), decreases in weight (5 kg), and reductions in insulin doses 3

Risk Mitigation If SGLT2 Inhibitors Are Used Off-Label

• Strict ketone monitoring protocols must be implemented 1
• Patient education about DKA symptoms (dyspnea, nausea, vomiting, abdominal pain) is essential 1, 2
• Patients should immediately stop taking SGLT2 inhibitors and seek medical attention if DKA symptoms develop 1
• Avoid use during periods of increased DKA risk: illness, reduced food intake, dehydration, alcohol consumption 1, 2
• Patients who have previously experienced DKA should not be treated with SGLT2 inhibitors under any circumstances 2

Potential Benefits of SGLT2 Inhibitors in T1DM

• Despite the risks, studies have shown that SGLT2 inhibitors in T1DM can provide:
  • Modest improvements in glycemic control 5, 6
  • Reduction in body weight 5, 6
  • Decrease in required insulin doses 5, 6
  • No increased risk of hypoglycemia 5

However, these benefits do not outweigh the significant risk of DKA in this population 1, 2.