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ACE inhibitors, statins do not reduce CV risks in adolescents with type 1 diabetes
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Albumin-to-creatinine ratio over time was not affected by ACE inhibitor or statin therapies in adolescents with type 1 diabetes, according to study findings published in the New England Journal of Medicine.
David B. Dunger, MD, FRCP, professor in the department of pediatrics at the University of Cambridge in the United Kingdom, and colleagues evaluated data from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) on 443 adolescents (mean age, 12.4 years) with type 1 diabetes to evaluate the effects of ACE inhibitors and statins. Participants were recruited between May 2009 and August 2013. Median follow-up was 2.6 years, and 154 participants completed the maximum 4 years.
A 2-by-2 factorial design was used to randomly assign participants to an ACE inhibitor (quinapril 5-10 mg per day), statin (atorvastatin 10 mg) and combinations of both or placebo.
The area under the curve (AUC) of the albumin-to-creatinine ratio was not significantly affected by the ACE inhibitor or statin, and there was no significant interaction between the two study drugs. The results were not altered by sensitivity analyses allowing for different levels of drug adherence and duration of treatment.
The cumulative incidence of microalbuminuria was reduced with the use of ACE inhibitors (adjusted HR = 0.57; 95% CI, 0.34-0.94); however, this was not thought to be significant in the context of the negative findings for the primary outcomes, according to the researchers. The statin had no effect on the incidence of microalbuminuria.
Lower levels of total, LDL and non-HDL cholesterol, and triglycerides and the ratio of apolipoprotein B to apolipoprotein A1 were associated with statin treatment; ACE inhibitors did not have a significant effect on lipid levels except for significantly higher HDL cholesterol levels.
No significant effects were observed for carotid intima-media thickness or the asymmetric dimethylarginine level with ACE inhibitor or statin treatment.
Four serious adverse reactions were related to ACE inhibitors; no serious adverse reactions were related to statins.
“Our trial assessed the effects of ACE-inhibitor and statin therapy in adolescents with type 1 diabetes, a group of patients who are difficult to recruit into and retain in clinical trials,” the researchers wrote. “The use of these agents over a period of 2 to 4 years did not show any effect on the primary outcome of a change in repeated measures of the albumin-to-creatinine ratio over time. This endpoint was chosen because previous longitudinal studies had shown that increases in the albumin-to-creatinine ratio during puberty, below the thresholds for microalbuminuria and microalbuminuria, were associated with risk markers for cardiovascular disease.” – by Amber Cox
Disclosures: Dunger reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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The AdDit study by Marcovecchio and colleagues tested whether adolescents with type 1 diabetes benefit in microalbuminuria risk by pretreatment with ACE inhibitors and/or statins. High-risk subjects (ie, those with high albumin-to-creatinine ratio) with HbA1c of 8% or more, most on pumps, were studied in a 2-by-2 design. ACE inhibitors (5-10 mg of quinapril) and/or a statin (10 mg of atorvastatin) were compared to placebo control. Follow-up was 2.4 years. The primary endpoint was albuminuria assessed at albumin-to-creatinine ratio every 6 months. Adherence was good (75%) and drop-outs were 18%. The primary endpoint was negative despite reduced albuminuria with ACE inhibitors. Secondary endpoints were also negative, including glomerular filtration rate, retinopathy progression, carotid intima-media thickness and other CV risk markers. There was no protection against microalbuminuria, an important risk for CV and renal disease. Several possible explanations were discussed. A short duration of treatment with follow-up for 2 to 4 years may simply not be long enough. Subjects may not have high risk. This primary prevention study might need larger numbers and longer treatment and follow-up. The study is maybe underpowered despite good adherence and moderate dropouts. Intervention duration might be too early or assessment of insufficient duration. Long-term follow-up of these subjects should be carried out to determine whether a legacy effect might exist. The study was negative, but the approach was thoughtful; future studies may be needed to show benefit of ACE inhibitors and statins with longer treatment time and longer follow-up.
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