Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy

  1. Tomas Berl, MD;
  2. Lawrence G. Hunsicker, MD;
  3. Julia B. Lewis, MD;
  4. Marc A. Pfeffer, MD, PhD;
  5. Jerome G. Porush, MD;
  6. Jean-Lucien Rouleau, MD;
  7. Paul L. Drury, MD, FRACP;
  8. Enric Esmatjes, MD;
  9. Donald Hricik, MD;
  10. Chirag R. Parikh, MD;
  11. Itamar Raz, MD;
  12. Philippe Vanhille, MD;
  13. Thomas B. Wiegmann, MD;
  14. Bernard M. Wolfe, MD, FRCPC;
  15. Francesco Locatelli, MD;
  16. Samuel Z. Goldhaber, MD;
  17. Edmund J. Lewis, MD; and
  18. for the Collaborative Study Group*
  1. From University of Colorado Medical School, Denver, Colorado; University of Iowa College of Medicine, Iowa City, Iowa; Vanderbilt University College of Medicine, Nashville, Tennessee; Brigham and Women's Hospital, Boston, Massachusetts; Brookdale University Hospital and Medical Center, Brooklyn, New York; University of Toronto, Toronto, Ontario, Canada; Auckland Diabetes Centre, Auckland, New Zealand; Hospital Clinic, University of Barcelona, Barcelona, Spain; Case Western Reserve University School of Medicine, Cleveland, Ohio; Hadassah University, Jerusalem, Israel; Centre Hospitalier de Valenciennes, Valenciennes, France; University of Kansas City Medical Center and College of Health Sciences, Veterans Affairs Medical Center, Kansas City, Kansas; University of Western Ontario, London, Ontario, Canada; Monzoni Hospital, Lecco, Italy; and Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois.

    Abstract

    Background: Patients with diabetes have increased risk for adverse cardiovascular events. Angiotensin-converting enzyme inhibitors are protective in type 1 diabetes. However, no definitive studies have examined the use of angiotensin-receptor blockers in patients with type 2 diabetes and overt nephropathy. The primary outcomes of the Irbesartan Diabetic Nephropathy Trial were doubling of serum creatinine levels, end-stage renal disease, and death from any cause.

    Objective: To compare rates of cardiovascular events among patients with type 2 diabetic nephropathy who received conventional antihypertensive therapy with an angiotensin-receptor blocker (irbesartan) or a calcium-channel blocker (amlodipine), or placebo.

    Design: Randomized double-blind, placebo-controlled trial with a median follow-up of 2.6 years. A time event analysis was used.

    Setting: 209 centers in the Americas, Europe, Israel, and Australasia.

    Participants: 1715 adults with type 2 diabetic nephropathy and hypertension; serum creatinine levels of 89 µmol/L (1.0 mg/dL) to 266 µmol/L (3.0 mg/dL) in women and 106 µmol/L (1.2 mg/dL) to 266 µmol/L (3.0 mg/dL) in men; and urinary protein excretion rates of at least 900 mg/d.

    Intervention: Treatment with irbesartan, amlodipine, or placebo.

    Measurements: Time to cardiovascular death, myocardial infarction, congestive heart failure, strokes, and coronary revascularization.

    Results: The three groups were not statistically different in the composite of cardiovascular events. Among the components of the composite, there was a trend toward a decrease in strokes in patients receiving amlodipine versus those receiving placebo (hazard ratio, 0.65 [95% CI, 0.35 to 1.22]; P = 0.18). Likewise, patients receiving amlodipine had a significantly lower rate of myocardial infarction when compared with placebo recipients (hazard ratio, 0.58 [CI, 0.37 to 0.92]; P = 0.02). In contrast, patients receiving irbesartan had a significantly lower incidence of congestive heart failure when compared with placebo recipients (hazard ratio, 0.72 [CI, 0.52 to 1.00]; P = 0.048) or amlodipine recipients (hazard ratio, 0.65 [CI, 0.48 to 0.87]; P = 0.004).

    Conclusion: The composite cardiovascular event rate did not differ in patients with type 2 diabetes and overt nephropathy treated with irbesartan, amlodipine, or placebo in addition to conventional antihypertensive therapy.

    *For members of the Collaborative Study Group, see the Appendix.

    Article and Author Information

    • Acknowledgments: The authors thank Deborah Anzalone, MD, and her staff at Bristol-Myers Squibb for their outstanding support throughout this study and Zafie Craft for her expert administrative assistance.

    • Grant Support: By Bristol-Myers Squibb Pharmaceutical Research Institute and Sanofi-Synthelabo.

    • Potential Financial Conflicts of Interest:Consultancies: T. Berl (Bristol-Myers Squibb), L.G. Hunsicker (Bristol-Myers Squibb and Sanofi-Synthelabo), J.B. Lewis (Bristol-Myers Squibb), M.A. Pfeffer (Bristol-Myers Squibb), J.G. Porush (Bristol-Myers Squibb), J.-L. Rouleau (Bristol-Myers Squibb), S.Z. Goldhaber (Bristol-Myers Squibb); Honoraria: T. Berl (Pfizer), L.G. Hunsicker (Bristol-Myers Squibb and Sanofi-Synthelabo), J.B. Lewis (Bristol-Myers Squibb), M.A. Pfeffer (Bristol-Myers Squibb), J.-L. Rouleau (Bristol-Myers Squibb), B.M. Wolfe (Bristol-Myers Squibb); Stock ownership or options (other than mutual funds): L.G. Hunsicker (Bristol-Myers Squibb); Expert testimony: M.A. Pfeffer (Bristol-Myers Squibb); Grants received: T. Berl (Pfizer), L.G. Hunsicker (Bristol-Myers Squibb and Sanofi-Synthelabo), J.B. Lewis (Bristol-Myers Squibb), M.A. Pfeffer (Bristol-Myers Squibb), J.G. Porush (Bristol-Myers Squibb), J.-L. Rouleau (Bristol-Myers Squibb), B.M. Wolfe (Bristol-Myers Squibb).

    • Requests for Single Reprints: Edmund J. Lewis, MD, Rush-Presbyterian-St. Luke's Medical Center, The Collaborative Study Group (CSG), 1750 West Harrison, Rawson Building, Room 522, Chicago, IL 60612; e-mail, csg{at}rush.edu.

    • Current Author Addresses: Drs. Berl and Parikh: University of Colorado, 4200 East 9th Avenue, Denver, CO 80262.

    • Dr. Hunsicker: University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242-1081.

    • Dr. J.B. Lewis: Vanderbilt University, 21st and Garland Avenues, Nashville, TN 37232-2372.

    • Drs. Pfeffer and Goldhaber: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

    • Dr. Porush: Brookdale University Hospital and Medical Center, 1 Brookdale Plaza, Brooklyn, NY 11212.

    • Dr. Rouleau: Toronto General Hospital, 200 Elizabeth, EN 13-212, Toronto, Ontario M5G 2C4, Canada.

    • Dr. Drury: Auckland Diabetes Centre, 5th Floor, 48 Greys Avenue, Auckland, New Zealand 1005.

    • Dr. Esmatjes: Hospital Clinic, University of Barcelona, Villarroel, 170, E-08036, Barcelona, Spain.

    • Dr. Hricik: University Hospital of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106.

    • Dr. Raz: Hadassah Hospital, Ein Kerem, Jerusalem, Israel.

    • Dr. Vanhille: Hospital de Valenciennes, Avenue Desandronin, Valenciennes, France 59322.

    • Dr. Wiegmann: Veterans Affairs Medical Center, 4901 Linwood, Kansas City, MO 64128.

    • Dr. Wolfe: University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B8, Canada.

    • Dr. Locatelli: A. Manzoni Hospital, Via D'remo 9/11, Lecco, Italy 23900.

    • Dr. E.J. Lewis: Rush-Presbyterian-St. Luke's Medical Center, The Collaborative Study Group (CSG), 1750 West Harrison, Rawson Building, Room 522, Chicago, IL 60612.

    • Author Contributions: Conception and design: T. Berl, L.G. Hunsicker, J.B. Lewis, M.A. Pfeffer, J.G. Porush, J.-L. Rouleau, P.L. Drury, I. Raz.

    • Analysis and interpretation of the data: T. Berl, L.G. Hunsicker, J.B. Lewis, M.A. Pfeffer, J.G. Porush, J.-L. Rouleau, P.L. Drury, I. Raz, S.Z. Goldhaber.

    • Drafting of the article: T. Berl, L.G. Hunsicker, J.B. Lewis, M.A. Pfeffer, J.G. Porush.

    • Critical revision of the article for important intellectual content: T. Berl, L.G. Hunsicker, J.B. Lewis, M.A. Pfeffer, J.G. Porush, J.-L. Rouleau, P.L. Drury, T.B. Wiegmann, F. Locatelli, S.Z. Goldhaber.

    • Final approval of the article: T. Berl, L.G. Hunsicker, J.B. Lewis, M.A. Pfeffer, J.-L. Rouleau, P.L. Drury, E. Esmatjes, D.E. Hricik, I. Raz, P. Vanhille, B.M. Wolfe, F. Locatelli, S.Z. Goldhaber.

    • Provision of study materials or patients: T. Berl, L.G. Hunsicker, J.G. Porush, J.-L. Rouleau, P.L. Drury, E. Esmatjes, D.E. Hricik, I. Raz, P. Vanhille, T.B. Wiegmann, B.M. Wolfe, F. Locatelli.

    • Statistical expertise: L.G. Hunsicker, C.R. Parikh.

    • Administrative, technical, or logistic support: T. Berl, T.B. Wiegmann.

    Summary for Patients

    • Summaries for Patients:Effects of Blood Pressure Drugs in Patients with Diabetes and Kidney Disease Ann Intern Med April 1, 2003 138:I-43
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    1. Ann Intern Med April 1, 2003 vol. 138 no. 7 542-549
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