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Clinical Trial
. 2022 May;10(5):341-350.
doi: 10.1016/S2213-8587(22)00052-3. Epub 2022 Apr 1.

Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study

William V Tamborlane  1 , Lori M Laffel  2 , Naim Shehadeh  3 , Elvira Isganaitis  2 , Michelle Van Name  4 , Jayantha Ratnayake  5 , Cecilia Karlsson  6 , Ensio Norjavaara  6
Affiliations
Clinical Trial

Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study

William V Tamborlane et al. Lancet Diabetes Endocrinol. 2022 May.

Abstract

Background: Since there are few treatment options for young people with type 2 diabetes, we aimed to assess the efficacy and safety of dapagliflozin as add-on therapy in children, adolescents, and young adults with type 2 diabetes receiving metformin, insulin, or both.

Methods: This multicentre, placebo-controlled, double-blind, randomised phase 3 study was undertaken at 30 centres in five countries (Hungary, Israel, Mexico, Russia, and the USA). Participants aged 10-24 years with type 2 diabetes and HbA1c concentration of 6·5-11% (48-97 mmol/mol) were randomly assigned 1:1 to oral dapagliflozin 10 mg or placebo during a 24 week double-blind period, which was then followed by a 28 week open-label safety extension in which all participants received dapagliflozin. Participants and study personnel were masked and participants were randomly assigned treatment (placebo or study drug) using an interactive web and voice response system. The primary outcome was between-group differences in change in HbA1c concentration from baseline to 24 weeks (intention-to-treat analysis). A prespecified sensitivity analysis of the primary outcome was also assessed in the per-protocol population, which included only protocol-compliant participants. This trial is registered with ClinicalTrials.gov, NCT02725593.

Findings: Between June 22, 2016, and March 15, 2019, 72 participants (19 [26%] of whom were aged 18-24 years) were randomly assigned (39 to dapagliflozin and 33 to placebo). Mean age was 16·1 (SD 3·3) years. In the intention-to-treat analysis, after 24 weeks, mean change in HbA1c concentration was -0·25% (95% CI -0·85 to 0·34; -2·7 [-9·3 to 3·7] mmol/mol) for dapagliflozin and 0·50% (-0·18 to 1·17; 5·5 [-2·0 to 12·8] mmol/mol) for placebo. The between-group difference was -0·75% (95% CI -1·65 to 0·15; -8·2 [-18·0 to 1·6] mmol/mol; p=0·10). In a sensitivity analysis in the per-protocol population (34 in the dapagliflozin group and 26 in the placebo group) after 24 weeks, mean change was -0·51% (-1·07 to 0·05; -5·6 [-11·7 to 0·5] mmol/mol) for dapagliflozin and 0·62% (-0·04 to 1·27; 6·8 [-0·4 to 13·9] mmol/mol) for placebo. The between-group difference was -1·13% (-1·99 to -0·26; -12·4 [-21·8 to -2·8] mmol/mol; p=0·012). Adverse events occurred in 27 (69%) dapagliflozin-assigned participants and 19 (58%) placebo-assigned participants over 24 weeks, and in 29 (74%) participants who received dapagliflozin over 52 weeks. Hypoglycaemia occurred in 11 (28%) dapagliflozin-assigned and six (18%) placebo-assigned participants who received dapagliflozin over 24 weeks and in 13 participants (33%) who received dapagliflozin over 52 weeks; none were considered as serious adverse events. No adverse events of diabetic ketoacidosis occurred.

Interpretation: The primary outcome of change in HbA1c concentration was not significant in the intention-to-treat analysis of children, adolescents, and young adults with type 2 diabetes receiving dapagliflozin in addition to standard-of-care treatment. A prespecified sensitivity analysis of protocol-compliant participants showed a significant difference in HbA1c concentration between groups. No new safety signals were identified and there was a low risk of severe hypoglycaemia.

Funding: AstraZeneca.

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Conflict of interest statement

Declaration of interests WVT has received consulting fees from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Medtronic Diabetes. LML has received consulting fees from Provention, Dompe, Insulet, Medtronic, Roche, Janssen, Eli Lilly, Convatec, Dexcom, and Novo Nordisk. NS has received grants for medical research from Novo Nordisk; has participated in a data safety monitoring board or advisory board for Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Sanofi, AstraZeneca and Abbott; has received consulting fees and payment or honoraria from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Sanofi, AstraZeneca, and Abbott; and has received support for attending meetings or travel from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Sanofi, and AstraZeneca. JR is an employee of AstraZeneca. CK and EN are employees and stockholders of AstraZeneca. EI and MVN declare no competing interests.

Figures

Figure 1:
Figure 1:. Participant disposition
*32/39 (82.1%) and 25/33 (75.8%) participants in the dapagliflozin and placebo groups, respectively, were still receiving study drug at the end of the double-blind short-term period; †30/39 (76.9%) and 24/33 (72.7%) participants, respectively, were still receiving open-label dapagliflozin treatment at the end of the long-term period; ITT=intent-to-treat; PP=per-protocol
Figure 2:
Figure 2:. Efficacy outcomes
(A) Primary outcome of adjusted mean change from baseline to Week 24 in HbA1c; (B) Sensitivity analysis of the primary outcome in the per-protocol population (excludes participants with relevant protocol deviations); (C) Secondary outcome of adjusted mean change from baseline to Week 24 in FPG; (D) Secondary outcome of proportion of participants with baseline HbA1c ≥7% who achieved HbA1c <7% at Week 24; Analyses exclude values after glycemic rescue or permanent discontinuation from study drug; The primary outcome did not achieve statistical significance in the ITT population and all other p-values should be considered as nominal p-values; DAPA=dapagliflozin; FPG=fasting plasma glucose; ITT=intent-to-treat
Figure 2:
Figure 2:. Efficacy outcomes
(A) Primary outcome of adjusted mean change from baseline to Week 24 in HbA1c; (B) Sensitivity analysis of the primary outcome in the per-protocol population (excludes participants with relevant protocol deviations); (C) Secondary outcome of adjusted mean change from baseline to Week 24 in FPG; (D) Secondary outcome of proportion of participants with baseline HbA1c ≥7% who achieved HbA1c <7% at Week 24; Analyses exclude values after glycemic rescue or permanent discontinuation from study drug; The primary outcome did not achieve statistical significance in the ITT population and all other p-values should be considered as nominal p-values; DAPA=dapagliflozin; FPG=fasting plasma glucose; ITT=intent-to-treat
Figure 2:
Figure 2:. Efficacy outcomes
(A) Primary outcome of adjusted mean change from baseline to Week 24 in HbA1c; (B) Sensitivity analysis of the primary outcome in the per-protocol population (excludes participants with relevant protocol deviations); (C) Secondary outcome of adjusted mean change from baseline to Week 24 in FPG; (D) Secondary outcome of proportion of participants with baseline HbA1c ≥7% who achieved HbA1c <7% at Week 24; Analyses exclude values after glycemic rescue or permanent discontinuation from study drug; The primary outcome did not achieve statistical significance in the ITT population and all other p-values should be considered as nominal p-values; DAPA=dapagliflozin; FPG=fasting plasma glucose; ITT=intent-to-treat
Figure 2:
Figure 2:. Efficacy outcomes
(A) Primary outcome of adjusted mean change from baseline to Week 24 in HbA1c; (B) Sensitivity analysis of the primary outcome in the per-protocol population (excludes participants with relevant protocol deviations); (C) Secondary outcome of adjusted mean change from baseline to Week 24 in FPG; (D) Secondary outcome of proportion of participants with baseline HbA1c ≥7% who achieved HbA1c <7% at Week 24; Analyses exclude values after glycemic rescue or permanent discontinuation from study drug; The primary outcome did not achieve statistical significance in the ITT population and all other p-values should be considered as nominal p-values; DAPA=dapagliflozin; FPG=fasting plasma glucose; ITT=intent-to-treat
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Comment in

  • Dapagliflozin in young people with type 2 diabetes.
    Tommerdahl KL, Nelson RG, Bjornstad P. Tommerdahl KL, et al. Lancet Diabetes Endocrinol. 2022 May;10(5):303-304. doi: 10.1016/S2213-8587(22)00075-4. Epub 2022 Apr 1. Lancet Diabetes Endocrinol. 2022. PMID: 35378070 Free PMC article. No abstract available.

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