The international AdDIT trial group have this month published results of a four year clinical trial in The New England Journal of Medicine, finding that ACE inhibitors and statins did not change the primary outcome – the albumin to creatinine ratio – compared to placebo in adolescents with type 1 diabetes (T1D).
People with type 1 diabetes (T1D) are at increased risk of developing long-term complications such as nephropathy, retinopathy and cardiovascular disease. While maintaining tight glucose control can reduce the risk of long term complications, there are many variables affecting blood glucose levels that make this extremely difficult and burdensome. Maintaining blood glucose levels is particularly difficult during the adolescent years.
Albumin is a protein that is normally found in the blood, but leaks into urine when kidney function is impaired. Rapid increases in albumin excretion during puberty precede the development of microalbuminuria, indicating early kidney damage, and subsequent macroalbuminuria, indicating more advanced kidney damage. As micro- and macroalbuminuria can take years to eventuate, the primary outcome for both interventions was the initial change in albumin excretion as the predictive marker of kidney damage. ACE inhibitors and statins are commonly used in adults to treat hypertension and hypercholesterolemia; however their use in adolescents has not been evaluated in T1D. The study group hypothesised that these drugs may be useful in reducing the risk of long term complications in adolescents with high levels of albumin excretion.
Over four years, the study team screened 4407 adolescents between 10-16 years from three countries (Australia, UK and Canada) and identified 1287 with values in the upper third of the albumin to creatinine ratios. The Australian arm of this study was led by CRN researcher Professor Tim Jones at the Telethon Kid’s Institute Children’s Diabetes Centre. The Children’s Diabetes Centre, co-directed by Professor Jones, is a NHMRC/JDRF funded Centre of Research Excellence.
Of the 1287 adolescents identified, 443 were randomly assigned to receive an ACE inhibitor, statin, a combination of the two, or a placebo. The primary outcome of albumin excretion was assessed according to the albumin-to-creatinine ratio calculated from three early-morning urine samples obtained every 6 months over 2 to 4 years.
Key secondary outcomes included markers of progressive kidney disease such as the development of microalbuminuria and changes in the glomerular filtration rate; markers of eye disease such as progression of retinopathy; markers of cardiovascular disease such as lipid levels, asymmetric dimethylarginine, carotid intima–media thickness and levels of high-sensitivity C-reactive protein.
The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of the ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo, however in the context of negative findings for the primary outcome, this did not reach the more stringent cut-off of p<0.01 for high significance (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). This finding is still of clinical relevance for future risk of kidney disease and was related to reduced variability in the albumin-creatinine ratio.
Statin use resulted in significant reductions in lipid levels, whereas neither drug had significant effects on carotid intima–media thickness, asymmetric dimethylarginine or carotid intima–media thickness the glomerular filtration rate, or progression of retinopathy.
Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups. This adherence rate is significantly higher than adherence rates in other adolescent cohorts which are commonly between 50-55%. This may be due to the relatively few reported side effects of the medications, and no pregnancies occurring throughout the trial.
The researcher group will be following the participants over the next 5-10 years to gain further insight into benefits of the drugs on long term complications.
Read more about Professor Tim Jones and his research here. He is currently leading the children and young people’s hybrid closed loop study in Australia, is one of the lead ADDN investigators, and is collaborating on various CRN, JDRF and other diabetes research projects.