In 10- to 16-year-olds with type 1 diabetes who were at risk of microalbuminuria, taking a statin or an ACE inhibitor or both for a few years did not significantly decrease albumin excretion compared with receiving placebo, in a new study.
Neither agent significantly reduced the albumin-to-creatinine ratio — the primary outcome — during the 2- to 4- year trial, senior author Prof David B Dunger, from the University of Cambridge, United Kingdom, told Medscape Medical News in an email.
“However, some of the secondary outcomes suggest that the drugs may have important benefits,” he noted. The trial showed that “treatment with ACE inhibitors and statins in adolescents with type 1 diabetes is safe and can lead to short-term [beneficial] effects on lipid levels and reduce rates of microalbuminuria.”
These findings from more than 400 participants in three countries, in the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT), by M Loredana Marcovecchio, from the University of Cambridge, and colleagues, were published in the November 2 issue of the New England Journal of Medicine.
Although the primary outcome of the study was negative, “effects on direct manifestations of renal, retinal, and cardiovascular complications are most likely to become apparent in the long term, during early adult life,” according to Dr Dunger.
Moreover, “early implementation of cardiorenal interventions in the AdDIT cohort might reduce long-term vascular complications through a similar ‘legacy effect’ reported in adults with diabetes treated with blood- and lipid-lowering drugs,” he speculated, but this would have to be determined in further study.
In the meantime, “these drugs should remain first-line therapy in adolescents with hypertension or hyperlipidemia but their use in high-risk individuals simply to provide cardiorenal protection is more controversial,” Dr Dunger summarized. “This may only be resolved through [ongoing] long-term follow-up of the AdDIT cohort.”
Could ACE Inhibitors, Statins Change Albumin Excretion in Teen T1D?
The efficacy and safety of ACE inhibitors and statins in adolescents have been shown in the context of hypertension and familial hypercholesterolemia, respectively, Dr Dunger explained.
But data are lacking on the long-term use of these drugs in adolescents with type 1 diabetes, in whom rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, and these changes are associated with dyslipidemia, hypertension, and other long-term risk factors for renal and cardiovascular disease.
Thus, the researchers hypothesized that such patients might benefit from ACE inhibitors and statins. AdDIT screened 4407 adolescents aged 10 to 16 who had type 1 diabetes at 32 centers in the United Kingdom, Canada, and Australia, from 2009 to 2013.
The researchers invited the 1287 adolescents with increased albumin excretion, defined as being in the upper third of albumin-to-creatinine ratios, and 443 agreed.
They were randomized to receive an ACE inhibitor (quinapril, 5 mg/day, titrated to 10 mg/day if tolerated at 2 weeks) plus placebo; statin (atorvastatin, 10 mg/day) plus placebo; both drugs plus placebo; or placebo alone, in a 2×2 factorial design — which was designed to minimize baseline differences in each study arm.
At baseline, the patients had a mean age of 12 and about 54% were boys.
They had a mean HbA1c of 8.3%, and close to half (47%) had had diabetes for less than 5 years; the rest had had it for 5 to 10 years.
The participants had a median urinary albumin-to-creatinine ratio of about 10.8 or an estimated 10.8-mg/day albumin excretion.
Fewer than 1% had microalbuminuria, defined as a urine albumin-to-creatinine ratio of 31.
The patients provided blood and urine samples at 1 month and 3 months and then on 3 consecutive days every 6 months for 2 to 4 years, over a median of 2.6 years.
ACE Inhibitor Reduced Microalbuminuria Risk, Statins Helped Lipids
There was no significant effect of the ACE inhibitor or the statin or both on the primary outcome, change in albumin excretion.
However, “treatment with the ACE inhibitor resulted in a 43% reduction in the rates of progression to microalbuminuria, which was not statistically significant, but it could have important clinical implications,” Dr Dunger noted.
“Preventing even intermittent cases of microalbuminuria is known to reduce the future risk of kidney and cardiovascular complications.”
Statin therapy was associated with significant reductions in total, LDL, and non–HDL cholesterol, and triglycerides and a lower apolipoprotein B-to-apolipoprotein A1 ratio, “which could reduce long-term risk for cardiovascular complications,” he added.
Neither drug had significant effects on carotid intima–media thickness, glomerular filtration rate, or progression of retinopathy.
Three quarters of the patients adhered to the drug regimen, and serious adverse events were similar across the groups.
“The main reservations for the early use of these drugs in young people with type 1 diabetes had been that they may be associated with side effects such as hypotension, cough, and hyperkalemia (ACE inhibitors) or myopathy and altered liver function (statins),” Dr Dunger said.
In the current trial, these drug types “emerged to be safe, with few side effects.” ACE-inhibitor treatment led to a few episodes of hypotension requiring dose reduction, and chronic cough was not a main concern. There were no major liver or muscle problems associated with statin treatment.
No pregnancies occurred during the trial period, but this remains an issue for ACE inhibitor and statin prescription in adolescents because of potential teratogenicity risks, he added.
Ongoing Study, “Vulnerable Group” of Young People With TID
The findings of reduced progression to microalbuminuria and reduced lipid levels “could translate into long-term benefits,” Dr Dunger stressed.
In the ongoing study of this unique cohort, “the essential biological samples and data provided by the participants will continue to inform our future understanding and our options for effective therapies for this vulnerable group of young people with type 1 diabetes.”
The study was supported by the JDRF, Diabetes UK, the British Heart Foundation, the JDRF Canadian Clinical Trial Network, the Canadian Diabetes Association, the Heart and Stroke Foundation of Canada, and by a grant (for retinopathy outcomes) from the National Health and Medical Research Council (Australia). Dr Dunger and Dr Marcovecchio report having no relevant financial relationships. Disclosures for the coauthors are listed in the paper.
N Engl J Med. 2017;377:1733-45. Article
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