From Pages to Practice
You have followed Adrian, a 14-year-old boy, for the past 5 years. Today, he visits you in clinic for a routine follow-up exam. He has had type 1 diabetes for 7 years and his father has had type 1 diabetes since age 10. Recently, Adrian has been struggling with adhering to his insulin needs because of increasing after-school activities and sports. His parents are worried about what they call “teen-age behavior.” They try to allow Adrian to manage his own diabetes, but he sometimes leaves his insulin pump at home and can’t remember where he last saw it. His exam this year reveals a HbA1C of 8.4% and microalbuminuria (albumin-to-creatinine ratio of 98), suggesting possible early chronic kidney disease. As a clinician, you wonder whether angiotensin-converting–enzyme (ACE) inhibitors would slow the progression of early diabetic nephropathy in adolescents, as has been documented in adults, and whether the addition of statins would decrease Adrian’s cardiovascular risk.
The Adolescent Type 1 Diabetes Cardio-renal Intervention Trial (AdDIT) trial, published this week in NEJM, addressed these questions. This pragmatic placebo-controlled clinical trial was designed to explore the risks and benefits of ACE inhibitors and statin treatment in adolescents at increased risk of diabetes-related complications (based on high urinary albumin-to-creatinine ratios).
Of 4407 screened adolescents, 1287 fell within the upper tertile of the albumin-creatinine ratios; 443 of these patients were randomized to receive an ACE inhibitor (quinapril, 5-10 mg/day), a statin (atorvastatin, 10 mg/day), combinations of both drugs, or placebo (using a 2x2 factorial design). The primary outcome was the change in albumin excretion, assessed by measurement of albumin-to-creatinine ratios on 3 consecutive days every 6 months over 2 to 4 years. Key secondary outcomes included the incidence of microalbuminuria, progression of retinopathy, and changes in glomerular filtration rate, lipid levels, and cardiovascular risk measures.
Adherence to study medications was 75%, and serious adverse events were similar across groups. Albumin excretion (the primary outcome) was not affected by ACE inhibitor therapy, statin therapy, or combination therapy. ACE-inhibitors reduced the risk of incident microalbuminuria (HR, 0.57; 95% CI, 0.35-0.94) and statin therapy was associated with significant reductions in total, LDL, non-HDL-cholesterol, and triglyceride levels and in the ApoB to ApoA1 ratio. However, neither statins nor ACE inhibitor therapy had significant effects on carotid intima-media thickness or other cardiovascular markers, glomerular filtration rate, or retinopathy progression. Mean HbA1c increased over time by about 0.5% in all groups, despite a high rate (50%) of insulin-pump therapy. Only 5% of participants were unable to tolerate the higher dose of ACE inhibitors by the end of the study, mainly due to hypotension.
The AdDIT study highlights some of the risks and benefits of early intervention for the prevention of micro and macrovascular complications of type 1 diabetes in a patient group that is difficult to recruit and retain in clinical trials. Treatment with ACE inhibitors and/or a statin over 2 to 4 years failed to show any effect on the primary outcome. Although changes in repeated measures of albumin-creatinine ratio over time were observed, and there was a 43% reduction in the rate of progression to microalbuminuria with ACE inhibitors, these findings were not statistically significant. Long-term follow up of this cohort will be important to assess whether intervention during adolescence, a critical period in development, has any long-term benefits.
You discuss these study results with your patient and his parents and defer adding further medications to his current regimen. You continue to encourage and counsel Adrian on strategies to help him adhere to the use of his insulin pump as a busy and increasingly independent adolescent. You will continue to follow him and the evolving evidence on possible renoprotective medications and cardiovascular-risk modifiers.