Oral SGLT2 induces ‘clinically meaningful’ HbA1c decrease for youths with type 2 diabetes

• Canagliflozin significantly reduced HbA1c levels compared to placebo in children and adolescents with type 2 diabetes.

• The drug showed a good safety profile, with no serious side effects attributed to it.

Study Overview & FDA Approval

Children and teens with type 2 diabetes showed a greater reduction in blood sugar (HbA1c) when treated with the oral SGLT2 inhibitor canagliflozin (Invokana, Janssen) than those receiving a placebo.

This finding supported the FDA’s decision in December 2024 to expand the drug’s approved use to include individuals aged 10 to 17 years. The approval was based on results from a phase 3 randomized controlled trial, recently published in the Annals of Internal Medicine.

Trial Details

• Participants: 171 youths (aged 10–17) with HbA1c between 6.5% and 11%, who had already been on a diet and exercise program for at least four weeks, with or without metformin.

• Design: After a 2-week preparation period, participants were randomly assigned to receive 100 mg canagliflozin (n = 84) or placebo (n = 87) once daily.

• At week 13, participants still above target HbA1c levels could either:

  • Continue 100 mg, or

  • Increase to 300 mg of canagliflozin.

• Duration: The study continued for one year.

• Main goals: Evaluate HbA1c changes and drug safety over 26 weeks.

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Results: Blood Sugar Control

• At 26 weeks, the canagliflozin group had a mean HbA1c reduction of –0.76 percentage points vs. placebo (P = .002).

• Among those also on metformin, results were similar (–0.77 percentage points, P = .012).

• Canagliflozin also led to a larger drop in fasting plasma glucose at:

  • 26 weeks: –25.5 mg/dL

  • 52 weeks: –27.8 mg/dL

Proportion of Patients Meeting HbA1c Targets:

• At 26 weeks:

  • HbA1c <6.5%: 36.3% (canagliflozin) vs. 14% (placebo)

  • HbA1c <7%: 45.7% vs. 32.8%

• At 1 year:

  • HbA1c <6.5%: 30.9% vs. 15.6%

  • HbA1c <7%: 47.2% vs. 28.9%

• Rescue medication was required by:

  • 46% of the placebo group

  • Only 11.9% of the canagliflozin group

• Body weight also declined more in the canagliflozin group (by 1.6 percentage points)

Safety Profile

• Adverse events: Reported in 77.4% (canagliflozin) vs. 74.7% (placebo).

  • More common side effects with canagliflozin:

    • Headache (10.7%)

    • Nasopharyngitis (9.5%)

    • UTIs (7.1%)

    • Vomiting (6%)

• Serious adverse events:

  • Canagliflozin: 9.5%

  • Placebo: 5.7%

  • Specific cases in canagliflozin group: One each of diabetic ketoacidosis, pancreatitis, and fracture (none attributed to the drug).

• Hypoglycemia (low blood sugar):

  • Symptomatic: 11.9% (canagliflozin) vs. 10.3% (placebo)

  • Glucose <70 mg/dL: 17.9% vs. 16.1%

  • Glucose <56 mg/dL: Similar between groups

  • Severe case: Only one, in placebo group

Clinical Perspective: A Step Forward

Experts Ryan P. Brady, MD and Amy S. Shah, MD from Cincinnati Children’s Hospital highlighted the trial as a meaningful development in managing youth-onset type 2 diabetes, a condition known to be more aggressive and challenging to manage than in adults.

• Canagliflozin’s effect on HbA1c lowering is comparable to that of GLP-1 receptor agonists.

• The editorial emphasized the need for combination therapy, given the high failure rate of single-agent treatments in youths.

• Brady noted that further research is needed to assess long-term impacts on cardiorenal health and disease progression in young populations.

Conclusion

Canagliflozin offers a safe and effective option for improving blood glucose control in children and adolescents with type 2 diabetes. Its ability to deliver sustained HbA1c reduction, possibly reduce body weight, and delay the need for additional medications makes it a valuable addition to pediatric diabetes