medwireNews: The first phase 3 trial of a sodium-glucose cotransporter (SGLT)2 inhibitor in children and young people with type 2 diabetes shows that dapagliflozin significantly improves their glucose control – as long as they remember to take it.
Analysis of the 24-week change in glycated hemoglobin (HbA1c) levels in the intention-to-treat population showed no significant difference between the 39 participants taking dapagliflozin 10 mg/day and the 33 taking placebo, at an average 0.25% (2.7 mmol/mol) decrease versus a 0.50% (5.5 mmol/mol) increase.
But there was a significant difference in the per-protocol population, with an average reduction of 0.51% (5.6 mmol/mol) in the 34 young people taking dapagliflozin versus a 0.62% (6.8 mmol/mol) increase for the 26 in the placebo group.
All but one of the participants excluded from the per-protocol population were so because they took less than 80% of their allocated medication.
In a commentary linked to the study in The Lancet Diabetes & Endocrinology, Petter Bjornstad (University of Colorado School of Medicine, Aurora, USA) and co-authors observe that “[t]he incongruent results between the intention-to-treat and compliance-based analyses are not unexpected, since young people have several barriers to medical adherence (including high rates of depression and poor motivation).”
The trial participants were aged between 10 and 24 years, with an average age of 16 years. Sixty percent were female, 61% White, and 60% had been diagnosed with diabetes less than 3 years previously. The majority (68%) had baseline HbA1c levels between 6.5% and 9% (48–75 mmol/mol), but 10% had lower levels and 22% higher, including two participants with HbA1c higher than 11% (97 mmol/mol). The average BMI was 32.4 kg/m2.
“A unique aspect of our study was the inclusion of a subset of young adult participants (18–24 years), an age range consistently under-represented in clinical trials in adults with type 2 diabetes,” say William Tamborlane (Yale University, New Haven, Connecticut, USA) and co-researchers.
In the per-protocol group, the significant improvement in HbA1c versus placebo was consistent regardless of sex, race, baseline HbA1c, and other glucose-lowering medications (51% were taking metformin, 17% insulin, and 32% both). Among people in the intention-to-treat population who initially had HbA1c higher than 7% (53 mmol/mol), 25% of those taking dapagliflozin had fallen below this threshold by week 24, compared with just 4% of the placebo group.
By contrast with trials in adults, treatment allocation had no significant effect on BMI, report the researchers
“This difference might reflect that the young participants were in (or had recently emerged from) puberty, in which considerable increases and fluctuations in growth, maturation, and development occur,” they suggest.
Hypoglycemia occurred in 28% of trial participants taking dapagliflozin and 18% of those taking placebo. Almost all events occurred in those who were also taking insulin, and the researchers say the difference in hypoglycemia rates between the two groups could be partly because of greater use of insulin in the dapagliflozin versus placebo groups (56 vs 39%).
There was one genital infection in a person taking dapagliflozin, which led to its discontinuation, but there were no cases of diabetic ketoacidosis.
“With an increasing population of young people with type 2 diabetes, there is an unmet need for additional treatment options that are effective, well tolerated, and easy to administer,” say Tamborlane and colleagues.
They believe their findings support the use of dapagliflozin as “the first oral glucose-lowering therapy since metformin” to show beneficial effects in this age group.
And they add that, given the poor cardiovascular risk profile in people with young-onset type 2 diabetes, “the non-glycaemic benefits of dapagliflozin reported in adults with or without type 2 diabetes, is an important consideration.”
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