Article    Table of Contents                    Full Text of this article    PDF of this article (PDFs free after 6 months)    Summary for Patients    Summary for Patients (PDF)    Figures/Tables List    Related articles in Annals  Services    Send comment/rapid response letter    Notify a friend about this article    Alert me when this article is cited    Add to Personal Archive    Download to Citation Manager    ACP Search                            Get Permissions  Google Scholar    Search for Related Content  PubMed Articles in PubMed by Author:    Berl, T.    Related Articles in PubMed    PubMed Citation    PubMed

ARTICLE

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

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, for the Collaborative Study Group*

1 April 2003 | Volume 138 Issue 7 | Pages 542-549

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.

Editors' Notes Context Previously published results of this randomized, double-blind trial showed that high-risk patients with type 2 diabetic nephropathy had better renal protection if they were treated with irbesartan rather than amlodipine in addition to conventional antihypertensive therapy. Contribution These detailed analyses showed no differences in overall cardiovascular outcomes between patients given irbesartan or amlodipine. Fewer patients given irbesartan had heart failure and fewer patients given amlodipine had heart attacks. Cautions The trial had limited power to detect important differences between groups in mortality or strokes, and most patients received several antihypertensive agents. –The Editors

 

Author and Article Information

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.

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.

Related articles in Annals:

Summaries for Patients
Effects of Blood Pressure Drugs in Patients with Diabetes and Kidney Disease

Annals 2003 138: I-43. [Full Text]  

This article has been cited by other articles:

				American Diabetes Association Standards of Medical Care in Diabetes--2008 Diabetes Care, January 1, 2008; 31(Supplement_1): S12 - S54. [Full Text] [PDF]

				R. E. Gilbert Rosiglitazone: Opening Pandora's Black Box? Clin. J. Am. Soc. Nephrol., November 1, 2007; 2(6): 1329 - 1331. [Full Text] [PDF]

				A. D. Naik, T. T. Issac, R. L. Street Jr, and M. E. Kunik Understanding the Quality Chasm for Hypertension Control in Diabetes: A Structured Review of "Co-maneuvers" Used in Clinical Trials J Am Board Fam Med, September 1, 2007; 20(5): 469 - 478. [Abstract] [Full Text] [PDF]

				K. D. Marciante, J. C. Bis, M. J. Rieder, A. P. Reiner, T. Lumley, S. A. Monks, C. Kooperberg, C. Carlson, S. R. Heckbert, and B. M. Psaty Renin-Angiotensin System Haplotypes and the Risk of Myocardial Infarction and Stroke in Pharmacologically Treated Hypertensive Patients Am. J. Epidemiol., July 1, 2007; 166(1): 19 - 27. [Abstract] [Full Text] [PDF]

				American Diabetes Association Standards of Medical Care in Diabetes--2007 Diabetes Care, January 1, 2007; 30(suppl_1): S4 - S41. [Full Text] [PDF]

				P. Ruggenenti, A. Perna, M. Ganeva, B. Ene-Iordache, G. Remuzzi, and for the BENEDICT Study Group Impact of Blood Pressure Control and Angiotensin-Converting Enzyme Inhibitor Therapy on New-Onset Microalbuminuria in Type 2 Diabetes: A Post Hoc Analysis of the BENEDICT Trial J. Am. Soc. Nephrol., December 1, 2006; 17(12): 3472 - 3481. [Abstract] [Full Text] [PDF]

				P. A Howard, J. W. Cheng, M. A Crouch, V. J Colucci, J. S Kalus, S. A Spinler, and M. Munger Drug Therapy Recommendations from the 2005 ACC/AHA Guidelines for Treatment of Chronic Heart Failure Ann. Pharmacother., September 1, 2006; 40(9): 1607 - 1616. [Abstract] [Full Text] [PDF]

				R. T. Tsuyuki and M. A. McDonald Response to Tsuyuki and McDonald Circulation, August 22, 2006; 114(8): 855 - 860. [Full Text] [PDF]

				P. S. Sever, N. R. Poulter, W. J. Elliott, M. C. Jonsson, H. R. Black, P. S. Sever, N. R. Poulter, W. J. Elliott, M. C. Jonsson, and H. R. Black Blood Pressure Reduction Is Not the Only Determinant of Outcome Circulation, June 13, 2006; 113(23): 2754 - 2774. [Full Text] [PDF]

				G. Remuzzi, M. Macia, and P. Ruggenenti Prevention and Treatment of Diabetic Renal Disease in Type 2 Diabetes: The BENEDICT Study J. Am. Soc. Nephrol., April 1, 2006; 17(4_suppl_2): S90 - S97. [Abstract] [Full Text] [PDF]

				R. E. Gilbert, K. Connelly, D. J. Kelly, C. A. Pollock, and H. Krum Heart Failure and Nephropathy: Catastrophic and Interrelated Complications of Diabetes Clin. J. Am. Soc. Nephrol., March 1, 2006; 1(2): 193 - 208. [Abstract] [Full Text] [PDF]

				M. Rahman, S. Pressel, B. R. Davis, C. Nwachuku, J. T. Wright Jr., P. K. Whelton, J. Barzilay, V. Batuman, J. H. Eckfeldt, M. A. Farber, et al. Cardiovascular Outcomes in High-Risk Hypertensive Patients Stratified by Baseline Glomerular Filtration Rate Ann Intern Med, February 7, 2006; 144(3): 172 - 180. [Abstract] [Full Text] [PDF]

				T. Berl and W. Henrich Kidney-Heart Interactions: Epidemiology, Pathogenesis, and Treatment Clin. J. Am. Soc. Nephrol., January 1, 2006; 1(1): 8 - 18. [Full Text] [PDF]

				American Diabetes Association Standards of Medical Care in Diabetes-2006 Diabetes Care, January 1, 2006; 29(suppl_1): S4 - S42. [Full Text] [PDF]

				G. Montalescot and J.-P. Collet Preserving cardiac function in the hypertensive patient: why renal parameters hold the key Eur. Heart J., December 2, 2005; 26(24): 2616 - 2622. [Abstract] [Full Text] [PDF]

				A. N. Friedman, L. G. Hunsicker, J. Selhub, A. G. Bostom, and for the Collaborative Study Group Total Plasma Homocysteine and Arteriosclerotic Outcomes in Type 2 Diabetes with Nephropathy J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3397 - 3402. [Abstract] [Full Text] [PDF]

				M. A McDonald, S. H Simpson, J. A Ezekowitz, G. Gyenes, and R. T Tsuyuki Angiotensin receptor blockers and risk of myocardial infarction: systematic review BMJ, October 15, 2005; 331(7521): 873. [Abstract] [Full Text] [PDF]

				M. A. Pohl, S. Blumenthal, D. J. Cordonnier, F. De Alvaro, G. DeFerrari, G. Eisner, E. Esmatjes, R. E. Gilbert, L. G. Hunsicker, J. B. L. de Faria, et al. Independent and Additive Impact of Blood Pressure Control and Angiotensin II Receptor Blockade on Renal Outcomes in the Irbesartan Diabetic Nephropathy Trial: Clinical Implications and Limitations J. Am. Soc. Nephrol., October 1, 2005; 16(10): 3027 - 3037. [Abstract] [Full Text] [PDF]

				Developed in Collaboration With the American Colle, Endorsed by the Heart Rhythm Society, S. A. Hunt, W. T. Abraham, M. H. Chin, A. M. Feldman, G. S. Francis, T. G. Ganiats, M. Jessup, M. A. Konstam, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult--Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure) J. Am. Coll. Cardiol., September 20, 2005; 46(6): 1116 - 1143. [Full Text] [PDF]

				S. A. Hunt, W. T. Abraham, M. H. Chin, A. M. Feldman, G. S. Francis, T. G. Ganiats, M. Jessup, M. A. Konstam, D. M. Mancini, K. Michl, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult--Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society Circulation, September 20, 2005; 112(12): 1825 - 1852. [Full Text] [PDF]

				J. Arnlov, J. C. Evans, J. B. Meigs, T. J. Wang, C. S. Fox, D. Levy, E. J. Benjamin, R. B. D'Agostino, and R. S. Vasan Low-Grade Albuminuria and Incidence of Cardiovascular Disease Events in Nonhypertensive and Nondiabetic Individuals: The Framingham Heart Study Circulation, August 16, 2005; 112(7): 969 - 975. [Abstract] [Full Text] [PDF]

				P. Verdecchia, G. Reboldi, F. Angeli, R. Gattobigio, M. Bentivoglio, L. Thijs, J. A. Staessen, and C. Porcellati Angiotensin-Converting Enzyme Inhibitors and Calcium Channel Blockers for Coronary Heart Disease and Stroke Prevention Hypertension, August 1, 2005; 46(2): 386 - 392. [Abstract] [Full Text] [PDF]

				F. Chiarelli, D. Di Marzio, F. Santilli, A. Mohn, A. Blasetti, F. Cipollone, A. Mezzetti, and A. Verrotti Effects of Irbesartan on Intracellular Antioxidant Enzyme Expression and Activity in Adolescents and Young Adults With Early Diabetic Angiopathy Diabetes Care, July 1, 2005; 28(7): 1690 - 1697. [Abstract] [Full Text] [PDF]

				T. Berl, L. G. Hunsicker, J. B. Lewis, M. A. Pfeffer, J. G. Porush, J.-L. Rouleau, P. L. Drury, E. Esmatjes, D. Hricik, M. Pohl, et al. Impact of Achieved Blood Pressure on Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial J. Am. Soc. Nephrol., July 1, 2005; 16(7): 2170 - 2179. [Abstract] [Full Text] [PDF]

				Blood Pressure Lowering Treatment Trialists' Colla Effects of Different Blood Pressure-Lowering Regimens on Major Cardiovascular Events in Individuals With and Without Diabetes Mellitus: Results of Prospectively Designed Overviews of Randomized Trials Arch Intern Med, June 27, 2005; 165(12): 1410 - 1419. [Abstract] [Full Text] [PDF]

				J. McMurray Angiotensin receptor blockers and myocardial infarction: Analysis of evidence is incomplete and inaccurate BMJ, May 28, 2005; 330(7502): 1269 - 1269. [Full Text] [PDF]

				E. J Lewis and on behalf of the Collaborative Study Group Angiotensin receptor blockers and myocardial infarction: Results reflect different cardiovascular states in patients with types 1 and 2 diabetes BMJ, May 28, 2005; 330(7502): 1269 - 1270. [Full Text]

				B. J Epstein and J. G Gums Angiotensin Receptor Blockers versus ACE Inhibitors: Prevention of Death and Myocardial Infarction in High-Risk Populations Ann. Pharmacother., March 1, 2005; 39(3): 470 - 480. [Abstract] [Full Text] [PDF]

				American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care, January 1, 2005; 28(suppl_1): S4 - S36. [Full Text] [PDF]

				Z. T. Bloomgarden Diabetes Complications Diabetes Care, June 1, 2004; 27(6): 1506 - 1514. [Full Text] [PDF]

				B. M. Brenner Regarding: "Management of Glomerular Proteinuria: A Commentary" J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1354 - 1355. [Full Text] [PDF]

				E. J. Lewis and J. B. Lewis ACE Inhibitors versus Angiotensin Receptor Blockers in Diabetic Nephropathy: Is There a Winner? J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1358 - 1360. [Full Text] [PDF]

				P. Trenkwalder Antihypertensive treatment with calcium channel blockers: pharmacological pornography or useful intervention? Nephrol. Dial. Transplant., January 1, 2004; 19(1): 17 - 20. [Full Text] [PDF]

				Standards of Medical Care in Diabetes Diabetes Care, January 1, 2004; 27(90001): s15 - 35. [Full Text] [PDF]

				T. Berl Angiotensin-Converting Enzyme Inhibitors versus AT1 Receptor Antagonist in Cardiovascular and Renal Protection: The case for AT1 Receptor Antagonist J. Am. Soc. Nephrol., January 1, 2004; 15(90010): S71 - 76. [Abstract] [Full Text]

				W. A. Wilmer, B. H. Rovin, C. J. Hebert, S. V. Rao, K. Kumor, and L. A. Hebert Management of Glomerular Proteinuria: A Commentary J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3217 - 3232. [Abstract] [Full Text] [PDF]

				I. Malik JournalScan Heart, July 1, 2003; 89(7): 815 - 816. [Full Text] [PDF]

				Treatment of Hypertension in Patients with Type 2 Diabetes Journal Watch Gastroenterology, May 28, 2003; 2003(528): 7 - 7. [Full Text]

				Treatment of Hypertension in Patients with Type 2 Diabetes Journal Watch Cardiology, May 16, 2003; 2003(516): 4 - 4. [Full Text]

				Treatment of Hypertension in Patients with Type 2 Diabetes Journal Watch (General), April 29, 2003; 2003(429): 1 - 1. [Full Text]