Dulaglutide vs insulin in adolescents with thalassaemia-induced diabetes: effect on metabolism and atherogenesis (DIADEMA)

Abstract

Abstract Aims/hypothesis Chronic iron overload represents a significant morbidity in transfusion-dependent β-thalassaemia (TDT), leading to various complications, including diabetes and CVDs. The glucagon-like peptide-1 receptor agonist dulaglutide has been approved for the treatment of type 2 diabetes in paediatrics. In addition, it was recently approved for the treatment of CVDs. Hence, this study aimed to assess the effect of dulaglutide compared with conventional insulin therapy on glycaemic metrics, pancreatic reserve, iron load and dyslipidaemia among adolescents with TDT-induced diabetes. Methods The open-label, parallel-group, randomised-controlled DIADEMA trial took place at the Paediatric Haematology Unit and the Paediatric and Adolescent Diabetes Unit, Paediatrics Hospital, Ain Shams University, Cairo, Egypt. Eligibility criteria were adolescents with TDT-induced diabetes aged 10–18 years, uncontrolled on metformin. The 80 participants were randomly assigned based on a computer-generated randomisation sequence to receive either subcutaneous dulaglutide (0.75 mg weekly) or conventional basal-bolus insulin therapy. Participants were followed up for 24 weeks with assessment of fasting blood glucose, HbA 1c , fructosamine, fasting C-peptide, continuous glucose monitoring (CGM)-derived metrics, haemolysis markers, serum ferritin and lipid profile. The primary efficacy endpoint was the change in the CV as an index for glycaemic variability from baseline to week 24. People assessing the outcomes were masked (blind) to group assignment. Results Both groups were similar as regards baseline clinico-laboratory characteristics ( p >0.05). After 24 weeks, dulaglutide resulted in a significant decrease in CV (from 39.45 ± 3.97% to 35.05 ± 4.30%; p <0.001), time above range, fasting blood glucose, HbA 1c , fructosamine, total cholesterol and serum ferritin, with a significant increase in fasting C-peptide and time in range compared with baseline levels and with the insulin group ( p <0.05). Although the glucose management indicator decreased in the insulin group after 24 weeks compared with baseline, the CV (from 39.85 ± 4.99% to 43.26 ± 5.75%; p <0.001) and time above range were significantly increased ( p <0.001). The estimated standardised effect size for the between-group difference in the CV was 1.69 (95% CI 1.16, 2.22). No serious adverse event was reported. Conclusions/interpretation The glucagon-like peptide-1 receptor agonist dulaglutide therapy was associated with greater improvements in glycaemic control and variability compared with insulin among adolescents with TDT-induced diabetes, without risk of hypoglycaemia or compromising safety. Moreover, dulaglutide might have a beneficial effect on iron overload, insulin secretion and lipid profile. These findings are exploratory and clinically provocative, warranting further investigation. Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Trial registration ClinicalTrials.gov NCT07370922.