Abstract | BACKGROUND: METHODS: In the double-blind, randomised, controlled ALTITUDE trial, 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease were randomly assigned (1:1) to receive aliskiren 300 mg per day or placebo as an adjunct to ACE inhibitors or ARBs. Randomisation was stratified on the basis of baseline urinary albumin-to- creatinine ratio and presence of cardiovascular disease history, and treatment assignments were masked to all patients and study staff. Patients were followed up for a median of 2·6 years (IQR 2·0-3·2). In our secondary analysis, we investigated prespecified intermediate renal outcomes of transitions in albuminuria stages (ie, transitions between normoalbuminuria, microalbuminuria, and macroalbuminuria) and rate of change of estimated glomerular filtration rate (eGFR). We investigated all outcomes in the intention-to-treat population. The primary composite renal outcome of ALTITUDE was defined as a sustained doubling of serum creatinine, end-stage renal disease, or renal death. The ALTITUDE trial is registered with ClinicalTrials.gov, number NCT00549757. FINDINGS:
Aliskiren significantly decreased progression (hazard ratio [HR] 0·83, 95% CI 0·75-0·93) and increased regression (HR 1·29, 95% CI 1·19-1·39) of transitions in albuminuria classes. The annual rate of change of eGFR was -3·1 mL/min/1·73 m(2) per year (95% CI -2·9 to -3·3) in the aliskiren group and -3·0 mL/min/1·73 m(2) per year (-2·8 to -3·2) in the placebo group (p=0·52). eGFR change during the first 6 months was significantly larger with aliskiren than with placebo (-2·5 mL/min/1·73 m(2), 95% CI -2·9 to -2·2 vs -1·4 mL/min/1·73 m(2), 95% CI -1·7 to -1·0; p<0·0001). Subsequent eGFR change did not differ significantly between groups (-2·8 mL/min/1·73 m(2) per year, 95% CI -3·0 to -2·6 with aliskiren vs -3·1 mL/min/1·73 m(2) per year, 95% CI -3·3 to -2·8 with placebo; p=0·068). The absence of a benefit of aliskiren on the primary composite renal endpoint in the overall population was also seen in various subgroups. INTERPRETATION:
Aliskiren showed no beneficial effect on hard renal outcomes in the overall population or in various subgroups, but delayed progression to microalbuminuria and macroalbuminuria, and improved regression to microalbuminuria and normoalbuminuria. Whether the chosen intermediates are poor surrogates for clinical outcomes or whether off-target effects disrupt the association between the surrogate and clinical outcomes requires further study. FUNDING: Novartis.
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Authors | Hiddo J L Heerspink, Frederik Persson, Barry M Brenner, Nish Chaturvedi, Patrick Brunel, John J McMurray, Akshay S Desai, Scott D Solomon, Marc A Pfeffer, Hans-Henrik Parving, Dick de Zeeuw |
Journal | The lancet. Diabetes & endocrinology
(Lancet Diabetes Endocrinol)
Vol. 4
Issue 4
Pg. 309-17
(Apr 2016)
ISSN: 2213-8595 [Electronic] England |
PMID | 26774608
(Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2016 Elsevier Ltd. All rights reserved. |
Chemical References |
- Amides
- Angiotensin Receptor Antagonists
- Antihypertensive Agents
- Fumarates
- aliskiren
- Creatinine
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Topics |
- Aged
- Albuminuria
(chemically induced, epidemiology)
- Amides
(adverse effects)
- Angiotensin Receptor Antagonists
- Antihypertensive Agents
- Creatinine
(urine)
- Diabetes Mellitus, Type 2
(complications, drug therapy)
- Double-Blind Method
- Female
- Follow-Up Studies
- Fumarates
(adverse effects)
- Glomerular Filtration Rate
- Humans
- Kidney Failure, Chronic
(chemically induced, epidemiology)
- Male
- Netherlands
(epidemiology)
- Prevalence
- Prognosis
- Survival Rate
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