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N Engl J Med. 2017 Nov 2;377(18):1733-1745. doi: 10.1056/NEJMoa1703518.

ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes.

Author information

1
From the Department of Paediatrics (M.L.M., D.B.D.) and the Wellcome Trust-Medical Research Council Institute of Metabolic Science (D.B.D.), University of Cambridge, and the Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital (S.B., S.D.), Cambridge, the National Centre for Cardiovascular Prevention and Outcomes, University College London (S.T.C., J.D.), and the WellChild Laboratory, Evelina London Children's Hospital, St. Thomas' Hospital (R.N.D.), London, the Institute of Cellular Medicine (Diabetes), Faculty of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne (S.M.M.), and the Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford (H.A.W.N.) - all in the United Kingdom; the Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto (D.D., F.H.M.); and the Institute of Endocrinology and Diabetes, Children's Hospital at Westmead and University of Sydney, Sydney (K.C.D.), and the Telethon Kids Institute, University of Western Australia, Perth (T.W.J.) - both in Australia.

Abstract

BACKGROUND:

Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long-term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin-converting-enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents.

METHODS:

We screened 4407 adolescents with type 1 diabetes between the ages of 10 and 16 years of age and identified 1287 with values in the upper third of the albumin-to-creatinine ratios; 443 were randomly assigned in a placebo-controlled trial of an ACE inhibitor and a statin with the use of a 2-by-2 factorial design minimizing differences in baseline characteristics such as age, sex, and duration of diabetes. The primary outcome for both interventions was the change in albumin excretion, assessed according to the albumin-to-creatinine ratio calculated from three early-morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve. Key secondary outcomes included the development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk (carotid intima-media thickness and levels of high-sensitivity C-reactive protein and asymmetric dimethylarginine).

RESULTS:

The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low-density lipoprotein, and non-high-density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima-media thickness, other cardiovascular markers, 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.

CONCLUSIONS:

The use of an ACE inhibitor and a statin did not change the albumin-to-creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476 .).

PMID:
29091568
DOI:
10.1056/NEJMoa1703518
[Indexed for MEDLINE]
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