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

Abstract

Background: The incidence of type 2 diabetes in young people is increasing, but treatments remain limited. We aimed to assess the efficacy and safety of an empagliflozin dosing regimen versus placebo and linagliptin versus placebo on glycaemic control in young people with type 2 diabetes.

Methods: In this double-blind, placebo-controlled trial done in 108 centres in 15 countries, participants with type 2 diabetes (aged 10-17 years; HbA_1c 6·5-10·5% [48-91 mmol/mol]) who had been previously treated with metformin or insulin were randomly assigned (1:1:1) to oral empagliflozin 10 mg, oral linagliptin 5 mg, or placebo. Participants in the empagliflozin group who did not have HbA_1c below 7·0% (<53 mmol/mol) by week 12 underwent a second double-blinded randomisation (1:1) at week 14, either remaining on 10 mg or increasing to 25 mg. Participants in the placebo group were randomly reassigned (1:1:1) in a double-blinded manner at week 26 to linagliptin 5 mg or one of the empagliflozin doses (10 mg or 25 mg). Investigators were masked throughout the trial and received assignments of blinded medication kits through interactive response technology for all participants at the initial randomisation and for the re-randomisations at weeks 14 and 26. The primary outcome was change from baseline in HbA_1c at 26 weeks. For empagliflozin, results were based on a pooled analysis for all participants on empagliflozin. Safety was assessed until week 52. This trial is registered with ClinicalTrials.gov, NCT03429543.

Findings: Between April 26, 2018, and May 26, 2022, of 262 screened participants, 158 (60%) were randomly assigned to treatment (53 [34%] to placebo, 52 [33%] to empagliflozin 10 mg, and 53 [34%] to linagliptin). For the primary outcome, the adjusted mean HbA_1c change from baseline at week 26 was -0·84% [-9·2 mmol/mol] in the empagliflozin pooled group versus placebo (95% CI -1·50 to -0·19 [-16·4 to -2·1]; p=0·012); the corresponding change from baseline for linagliptin versus placebo was -0·34% [-3·8 mmol/mol; 95% CI -0·99 to 0·30 [-10·8 to 3·3]; p=0·29). Adverse events occurred in 34 (64%) participants in the placebo group, 40 (77%) in the empagliflozin pooled group, and 37 (71%) in the linagliptin group, up to week 26. Of these, severe adverse events were reported in two (4%) participants in the placebo group, one (2%) in the empagliflozin pooled group, and one (2%) in the linagliptin group. Hypoglycaemia was the most frequently reported adverse event with higher rates for those on active drug treatment compared with placebo. No severe hypoglycaemia cases were reported.

Interpretation: Empagliflozin provided clinically relevant placebo-corrected reductions in HbA_1c, whereas linagliptin did not, and might offer a new treatment option for young people with type 2 diabetes.

Funding: The Boehringer Ingelheim and Eli Lilly and Company Alliance.

Figure 1:. Participant recruitment and disposition

TG1 population. Among those discontinuing treatment before week 26, on-treatment HbA1c was available for 1 participant. Reasons for discontinuation of empagliflozin treatment described as ‘other reasons’ included: 1. Exclusionary lab was received more than 2 weeks after randomisation, participant was discontinued per sponsor. 2. Principal investigator decision to discontinue due to non-compliance. 3. Participant has decided to stop taking study medication and, following the study protocol, participant was willing to attend visit 8 only. 4. Despite many attempts to contact participant, person lost to follow-up. HbA1c, glycated haemoglobin; mITT, modified intention-to-treat; TG, treatment groupings (see Treatment group definitions in this Supplementary Appendix for detailed explanation).

Figure 2:. Change in HbA1c from baseline to week 26 and week 52.

A. Descriptive data reflecting mean HbA1c over time from baseline to week 52 for empagliflozin versus placebo. mITT (TG1, TG5) (OC-AD) population. *Placebo treatment stopped at week 26. B. Descriptive data reflecting mean HbA1c over time from baseline to week 52 for linagliptin versus placebo. mITT (TG1, TG5) (OC-AD) population. *Placebo treatment stopped at week 26. To convert the values for % HbA1c to millimoles per mol, subtract 2·15 and multiply the result by 10·929. Empa, empagliflozin; HbA1c; glycated haemoglobin; OC-AD, observed cases (all data, including values after treatment discontinuation and after rescue therapy); Lina, linagliptin; SD, standard deviation; SE, standard error; TG, treatment groupings (see Supplementary Appendix for detailed explanation)

Figure 2:. Change in HbA1c from baseline to week 26 and week 52.

A. Descriptive data reflecting mean HbA1c over time from baseline to week 52 for empagliflozin versus placebo. mITT (TG1, TG5) (OC-AD) population. *Placebo treatment stopped at week 26. B. Descriptive data reflecting mean HbA1c over time from baseline to week 52 for linagliptin versus placebo. mITT (TG1, TG5) (OC-AD) population. *Placebo treatment stopped at week 26. To convert the values for % HbA1c to millimoles per mol, subtract 2·15 and multiply the result by 10·929. Empa, empagliflozin; HbA1c; glycated haemoglobin; OC-AD, observed cases (all data, including values after treatment discontinuation and after rescue therapy); Lina, linagliptin; SD, standard deviation; SE, standard error; TG, treatment groupings (see Supplementary Appendix for detailed explanation)