Effect of Candesartan on Microalbuminuria and Albumin Excretion Rate in Diabetes

Three Randomized Trials

  1. Rudy Bilous, MD;
  2. Nish Chaturvedi, MD;
  3. Anne Katrin Sjølie, MD;
  4. John Fuller, MD;
  5. Ronald Klein, MD;
  6. Trevor Orchard, MD;
  7. Massimo Porta, MD; and
  8. Hans-Henrik Parving, MD*
  1. From Newcastle University, Newcastle upon Tyne, United Kingdom; South Tees Hospitals NHS Trust and James Cook University Hospital, Middlesbrough, United Kingdom; International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College Healthcare NHS Trust, and University College London, London, United Kingdom; Odense University Hospital, Odense, Denmark; University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; University of Pittsburgh, Pittsburgh, Pennsylvania; University of Turin, Turin, Italy; and Rigshospitalet, University of Copenhagen, and Aarhus University, Copenhagen, Denmark.

    Abstract

    Background: Microalbuminuria in diabetes is strongly predictive of nephropathy, end-stage renal disease, and premature cardiovascular morbidity and mortality. Effective preventive therapies are therefore a clinical priority.

    Objective: To determine whether the angiotensin-receptor blocker candesartan compared with placebo affects microalbuminuria incidence or rate of change in albuminuria in type 1 and type 2 diabetes.

    Design: 3 randomized trials of the DIRECT (Diabetic Retinopathy Candesartan Trials) Program.

    Setting: 309 secondary care centers.

    Patients: 3326 and 1905 patients with type 1 and type 2 diabetes, respectively. Most were normotensive, and all had normoalbuminuria (median urinary albumin excretion rate, 5.0 µg/min).

    Intervention: Candesartan, 16 mg/d increasing to 32 mg/d, versus placebo. Assignment was done centrally using an interactive voice-response system. Patients, caregivers, and researchers were blinded to treatment assignment. During a median follow-up of 4.7 years, 793 patients discontinued therapy and 63 were lost to follow-up.

    Measurements: Urinary albumin excretion rate, assessed annually by 2 overnight collections; if it was 20 µg/min or greater, then 2 further collections were done. The primary end point was new microalbuminuria (3 or 4 collections of urinary albumin excretion rate ≥20 µg/min). The secondary end point was rate of change in albuminuria.

    Results: Individual and pooled results of the 3 trials showed that candesartan had little effect on risk for microalbuminuria (pooled hazard ratio, 0.95 [95% CI, 0.78 to 1.16]; P = 0.60). Pooled results showed that the annual rate of change in albuminuria was 5.53% lower (CI, 0.73% to 10.14%; P = 0.024) with candesartan than with placebo.

    Limitations: Investigators recruited mainly normotensive patients or patients with well-controlled hypertension who were at low overall vascular risk, which resulted in a low rate of microalbuminuria. Studies were powered for retinal and not renal end points.

    Conclusion: Candesartan, 32 mg/d, for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes.

    Primary Funding Source: AstraZeneca and Takeda.

    Article and Author Information

    • The results were presented at the 44th Annual Meeting of the European Association for the Study of Diabetes, Rome, Italy, 7–11 September 2008, and at the American Society of Nephrology Renal Week, Philadelphia, Pennsylvania, 4–9 November 2008.

    • Acknowledgment: The authors thank the HOPE Study investigators for supplying the unpublished data in Table 5.

      View this table:
      Table 5. Comparison of Studies in Patients With Type 1 and Type 2 Diabetes

    • Grant Support: By AstraZeneca and Takeda.

    • Potential Financial Conflicts of Interest: Consultancies: R. Bilous (AstraZeneca, Takeda, Roche, Johnson & Johnson, Novartis, GlaxoSmithKline, Bristol-Myers Squibb), N. Chaturvedi (AstraZeneca, Takeda), A.K. Sjølie (AstraZeneca, Takeda), J. Fuller (AstraZeneca, Takeda), T. Orchard (AstraZeneca, Takeda), M. Porta (AstraZeneca, Takeda), H.H. Parving (Novartis, Merck & Co., Pfizer, Sanofi-Aventis, AstraZeneca). Honoraria: R. Bilous (Bristol-Myers Squibb, GlaxoSmithKline, Roche, Takeda, AstraZeneca, Novartis, Johnson & Johnson), N. Chaturvedi (AstraZeneca, Takeda), A.K. Sjølie (AstraZeneca, Takeda), J. Fuller (Takeda, AstraZeneca), R. Klein (AstraZeneca, Lilly, Novartis, Pfizer), T. Orchard (AstraZeneca, Takeda), M. Porta (AstraZeneca, Takeda), H.H. Parving (Novartis, Merck & Co., Pfizer, Sanofi-Aventis, AstraZeneca). Stock ownership or options (other than mutual funds): T. Orchard (Bristol-Myers Squibb), H.H. Parving (Merck & Co., Novo Nordisk). Members of the steering committee received an annual honorarium/consultancy fee from the funding companies (AstraZeneca and Takeda).

    • Reproducible Research Statement: Study protocol: A description of the protocol has been published (10). The full version is available at http://www.clinicaltrials.gov. Statistical code: Not available. Data set: Main results (but not individual data) are available at http://www.direct-results.org.

    • Requests for Single Reprints: Rudy Bilous, MD, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, United Kingdom; e-mail, rudy.bilous{at}stees.nhs.uk.

    • Current Author Addresses: Dr. Bilous: Newcastle University, South Tees Hospitals NHS Trust, Academic Centre, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, United Kingdom.

    • Dr. Chaturvedi: International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College Healthcare NHS Trust, London W2 1PG, United Kingdom.

    • Dr. Sjølie: Department of Clinical Ophthalmology, Odense University Hospital, DK-5000 Odense C, Denmark.

    • Dr. Fuller: Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, United Kingdom.

    • Dr. Klein: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, University Avenue, Madison, WI 53726.

    • Dr. Orchard: Graduate School of Public Health, Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15213.

    • Dr. Porta: Department of Internal Medicine, University of Turin, Corso AM Dogliotti, I-10126 Turin, Italy.

    • Dr. Parving: Rigshospitalet, Department of Medical Endocrinology, University of Copenhagen, Blegdamsvej 9, DK 2100, Copenhagen, Denmark.

    • Author Contributions: Conception and design: R. Bilous, N. Chaturvedi, A.K. Sjølie, J. Fuller, T. Orchard, M. Porta, H.H. Parving.

    • Analysis and interpretation of the data: R. Bilous, N. Chaturvedi, A.K. Sjølie, J. Fuller, T. Orchard, M. Porta, H.H. Parving.

    • Drafting of the article: R. Bilous, N. Chaturvedi, A.K. Sjølie, J. Fuller, M. Porta.

    • Critical revision of the article for important intellectual content: R. Bilous, N. Chaturvedi, A.K. Sjølie, J. Fuller, R. Klein, T. Orchard, H.H. Parving.

    • Final approval of the article: R. Bilous, N. Chaturvedi, A.K. Sjølie, J. Fuller, R. Klein, T. Orchard, M. Porta, H.H. Parving.

    • Provision of study materials or patients: R. Bilous, N. Chaturvedi, A.K. Sjølie, M. Porta.

    • Obtaining of funding: R. Bilous, N. Chaturvedi, J. Fuller.

    • Administrative, technical, or logistic support: T. Orchard.

    • Collection and assembly of data: N. Chaturvedi, A.K. Sjølie, J. Fuller.

    • ClinicalTrials.gov registration numbers: NCT00252733, NCT00252720, and NCT00252694.

    • ↵* For a list of members and investigators of the DIRECT (Diabetic Retinopathy Candesartan Trials) Program Study Group, see the Appendix.

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