Tomas Berl, MD; Lawrence G. Hunsicker, MD; Julia B. Lewis, MD; Marc A. Pfeffer, MD, PhD; Jerome G. Porush, MD; Jean-Lucien Rouleau, MD; Paul L. Drury, MD, FRACP; Enric Esmatjes, MD; Donald Hricik, MD; Chirag R. Parikh, MD; Itamar Raz, MD; Philippe Vanhille, MD; Thomas B. Wiegmann, MD; Bernard M. Wolfe, MD, FRCPC; Francesco Locatelli, MD; Samuel Z. Goldhaber, MD; Edmund J. Lewis, MD; Collaborative Study Group*
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, firstname.lastname@example.org.
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.
Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau J, et al. Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial of Patients with Type 2 Diabetes and Overt Nephropathy. Ann Intern Med. 2003;138:542-549. doi: 10.7326/0003-4819-138-7-200304010-00010
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Published: Ann Intern Med. 2003;138(7):542-549.
Patients with diabetes have an increased risk for cardiovascular complications and death (1). Studies that analyzed the effects of inhibition of the renin–angiotensin system on the risk for cardiovascular complications included a substantial number of patients with diabetes (2-5) or were done exclusively in patients with diabetes (6-8). The meta-analysis of these studies (9), the analysis of the diabetic cohorts in the Heart Outcomes Prevention Evaluation (HOPE) study (2), and the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial (5) demonstrated that angiotensin-converting enzyme (ACE) inhibitors (2, 9) and angiotensin-receptor blockers (5) had a statistically significant advantage over placebo or alternative agents in decreasing the risk for several cardiovascular events. These studies randomly assigned few patients with renal involvement and overt proteinuria. Overt proteinuria occurred in fewer than 20% of the 470 patients in the Appropriate Blood Pressure Control in Diabetes (ABCD) trial (6), and only 11% of the 1195 patients in the LIFE trial (5). The Captopril Prevention Project (CAPP) (3) and the Swedish Trial in Old Patients with Hypertension-2 (STOP Hypertension-2) (4) did not state the number of patients with diabetes and overt proteinuria. There were no such patients in the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) (7), and patients with dipstick-positive albuminuria were excluded from the HOPE trial (2). Since proteinuria is an independent risk factor for cardiovascular disease (10, 11), the data obtained in the aforementioned trials cannot be extrapolated to patients with type 2 diabetes and overt nephropathy. Trials performed in such patients have reported a blood pressure–independent effect of two different angiotensin-receptor blocker agents to protect against nephropathy (12, 13) without a change in all-cause mortality. Apart from studies in heart failure, few cardiovascular data exist for receptor blockers compared with either placebo or calcium-channel blockers. We report on the analysis of the cardiovascular end points that were monitored as secondary end points in the Irbesartan Diabetic Nephropathy Trial (IDNT) (12) and assess whether an angiotensin II receptor blocker or a calcium-channel blocker alters the risk for cardiovascular events beyond those observed by blood pressure reduction alone without such agents.
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Cardiology, Endocrine and Metabolism, Hospital Medicine, Nephrology, Diabetes.
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