Dapagliflozin in young people with type 2 diabetes

Commentary:

Clinical trials in young persons with type 2 diabetes (T2D) are scarce, which is why the trial data presented by Tamborlane et al. evaluating the effects of a novel adjunctive T2D medication provide important therapeutic insight into this burgeoning, high-risk and understudied population.¹ Nearly 14 million youth in the United States are obese and at increased risk for youth-onset T2D.² Rising rates of obesity and other metabolic conditions are projected to increase the incidence of youth-onset T2D by 600% between 2017 and 2060.^2,3 The more severe metabolic phenotype observed in youth-onset vs. adult-onset T2D, including greater insulin resistance and more rapid deterioration of pancreatic β-cell function,⁴ increases their risk for the micro- and macrovascular complications of diabetes.⁵ Indeed, kidney biopsies obtained from Pima Indians with T2D document more severe kidney structural lesions in youth than adult-onset T2D irrespective of age and diabetes duration.⁶ Despite the burden of complications in youth-onset T2D, current therapeutic options are limited.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are highly effective therapies that significantly reduce the risk of heart and kidney disease in adults with T2D,⁷ but at present these medications are not approved by the FDA for persons younger than 18 years old. The Treatment Options for T2D in Adolescents and Youth (TODAY) and Restoring Insulin Secretion (RISE) trials have demonstrated differing physiology in adult-onset vs. youth-onset T2D indicating that dedicated clinical trials in young persons with youth-onset T2D are needed.⁴

Tamborlane et al. presented data from the first phase 3 placebo-controlled randomized trial of the SGLT2 inhibitor dapagliflozin, when added to standard of care (i.e., metformin, insulin, or both) in young persons with T2D (16.1 ± 3.4 years). The primary outcome of the trial was change in hemoglobin A1c (HbA1c) over 24 weeks. The intention-to-treat analysis did not demonstrate a statistically significant change in HbA1c between the dapagliflozin and placebo groups (−0.75 [95% CI −1.64, 0.15] %, p=0.10), but a pre-specified analysis of protocol-compliant participants documented a statistically significant decrease in HbA1c in response to dapagliflozin (−1.13 [−1.99, −0.26] %, p=0.01). This relative decrease in HbA1c was clinically significant and in line with that observed in adults with T2D. The incongruent results between the intention-to-treat and compliance-based analyses are not unexpected, since young persons with T2D face several barriers to medical adherence including high rates of depression and poor motivation.⁸ Hypoglycemia was documented in 28% of the participants receiving dapagliflozin and in 18% of those receiving placebo. The authors did not report any episodes of diabetic ketoacidosis (DKA). In contrast with adult trials, no statistically significant effects were noted in this study for secondary endpoints including changes in body mass index or blood pressure. These differences could be ascribed in part to normal growth fluctuations related to puberty and/or the low baseline prevalence of hypertension in this trial.

Considering the strong kidney protective effects of SGLT2 inhibition, a limitation of the trial was the absence of serial measures of albuminuria and estimated glomerular filtration rate (eGFR). A previous study in youth with T2D found that a single dose of SGLT2 inhibitor increased natriuresis and attenuated eGFR, findings consistent with adult data and demonstrating the need for long-term evaluation in pediatrics.⁹ Ongoing SGLT2 inhibitor trials in young persons with T2D that include changes in albuminuria and eGFR as additional endpoints will help establish the efficacy of SGLT2 inhibitors in mitigating diabetic kidney disease risk in this population.

The recently completed Treatment Options for Type 2 Diabetes in Adolescents and Youth follow-up study (TODAY/TODAY2) documented poor glycemic control and a high burden of vascular complications as adolescents with T2D enter young adulthood, a time that otherwise could be the most productive period of their lives.⁵ These serious data underscore the need for additional therapies, such as SGLT2 inhibitors, to improve metabolic and vascular health in these young persons with T2D. Future studies should leverage advances in integrative biology to define the mechanisms of benefit afforded by SGLT2 inhibition. This approach will help inform strategies for combination therapy and target the treatment to individuals with T2D who will most likely respond to these therapies.