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Pediatric type 2 diabetes: Expanding the horizons for empagliflozin

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Dr Sanjay Kalra, DM (AIIMS); President-elect, SAFES, Bharti Hospital, Karnal, India; Dr Mohan T Shenoy, Consultant Endocrinologist, SGMC, Venjaramoodu, Trivandrum    08 February 2023

Treatment with empagliflozin significantly reduced glycosylated hemoglobin (HbA1c) and blood glucose levels resulting in enhanced glycemic control in children and adolescents with type 2 diabetes, according to the results of the phase 3 DINAMO (DIabetes study of liNAgliptin and eMpagliflozin in children and adOlescents) trial published in The Lancet Diabetes & Endocrinology.1

 

Researchers from Germany and the United States collaborated in this multicountry, multicenter, double-blind, placebo-controlled trial to compare the safety and efficacy of empagliflozin (SGLT2 inhibitor) and linagliptin (DPP-4 inhibitor) versus placebo in 158 patients, aged 10-17 years, with type 2 diabetes. The participants had been taking either metformin or insulin; their HbA1c levels ranged from 6.5% to 10.5% (average 8%) and the BMI was in at least the 85th percentile for their age and sex. They were randomly assigned (1:1:1) to receive oral empagliflozin 10 mg (n=53), oral linagliptin 5 mg (n=52) or placebo (n=53)for 26 weeks. Patients who did not attain HbA1c levels below 7.0% at 12 weeks were again randomized to empagliflozin treatment, either 10 mg or 25 mg at 14 weeks for the remainder of the study duration. Similarly, the placebo recipients were randomly shifted (1:1:1) to either linagliptin (5 mg) or empagliflozin (10/25 mg) at week 26 in a double-blinded design.

 

Results showed that the change in the adjusted mean HbA1c, the primary endpoint of the study, with empagliflozin at week 26 was -0·84% compared to placebo. This reduction was statistically significant (P =.012). Empagliflozin also significantly reduced the fasting plasma glucose (-35.2mg/dL) at week 26, the secondary endpoint of the study (P =.0035). In the linagliptin group, the change in the adjusted mean HbA1c compared to placebo group was -0·34%, which was statistically non-significant (p=0·29).

 

The occurrence of adverse events was comparable across all the three groups; 34 placebo recipients reported adverse events vs 40 in the empagliflozin group vs 37 in the linagliptin-treated group. While hypoglycemia was the most frequent adverse event occurring in 19–23% of participants taking either empagliflozin / linagliptin vs 9% of those in the placebo group, severe hypoglycemia did not occur.

 

These results show that treatment with empagliflozin, but not linagliptin, led to a significant improvement in glycemic control in children and adolescents with type 2 diabetes. Therapeutic options for youth-onset type 2 diabetes are limited. Moreover, treatment failure rates are high and complications occur much earlier and more rapidly vis a vis type 2 diabetes in adulthood.2 Currently, oral metformin and the recently approved injectable liraglutide (glucagon-like peptide-1 analog) are the only approved treatments for pediatric type 2 diabetes. The FDA has added a Boxed Warning about the risk of thyroid C-cell tumors for liraglutide.3 Hence, there is a perceived need for more antidiabetic drugs, especially oral medications to treat type 2 diabetes in children and adolescents. The findings of the DINAMO trial expand the armamentarium of the treating physician and suggest the SGLT2 inhibitor empagliflozin as a new safe and effective treatment option for the management of type 2 diabetes in the youth.

 

Empagliflozin was FDA approved as treatment for type 2 diabetes in 2014. Later in 2016, it was approved to reduce risk of cardiovascular death in adults with type 2 diabetes. Recently in 2021, empagliflozin was sanctioned for use in adults with heart failure with reduced ejection fraction. Last year, it was approved for use across all categories of heart failure regardless of the left ventricular ejection fraction. The cardiorenal benefits of empagliflozin in patients with CKD were demonstrated in the EMPA-KIDNEY phase 3 trial, though it has not yet been granted approval for this indication.

 

 

References

 

  1. Lori M Laffel, et al; DINAMO Study Group Collaborators. Efficacy and safety of the SGLT2 inhibitor empagliflozin versus placebo and the DPP-4 inhibitor linagliptin versus placebo in young people with type 2 diabetes (DINAMO): a multicentre, randomised, double-blind, parallel group, phase 3 trial. Lancet Diabetes Endocrinol. 2023 Feb 1;S2213-8587(22)00387-4. doi: 10.1016/S2213-8587(22)00387-4.
  2. Serbis A, et al. Diagnosis, treatment and prevention of type 2 diabetes mellitus in children and adolescents. World J Diabetes. 2021 Apr 15;12(4):344-365. doi: 10.4239/wjd.v12.i4.344.
  3. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-pediatric-patients-type-2-diabetes, June 17, 2019. Accessed on Feb.7, 2023.

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