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Telmisartan is more effective than losartan in reducing proteinuria in patients with diabetic nephropathy

2008; Elsevier BV; Volume: 74; Issue: 3 Linguagem: Inglês

10.1038/ki.2008.204

1523-1755

George L. Bakris, Ellen Burgess, Jiang He, Giora Davidai, Stephen Koval,

Renal and Vascular Pathologies

In patients with diabetic nephropathy, lowering blood pressure and reducing proteinuria by over 30% correlates with a slower progression to kidney failure. We compared two different angiotensin receptor-blockers in a double blind, prospective trial of 860 patients with type 2 diabetes whose blood pressure levels was over 130/80 mmHg or who were receiving antihypertensive medication(s) and who had a morning spot urinary protein to creatinine ratio of 700 or more. Patients were randomized to telmisartan (a highly lipophilic agent with a long half-life) or losartan (with low lipophilicity and short half-life). The primary endpoint was the difference in the urinary albumin to creatinine ratio between the groups at 52 weeks. The geometric coefficient of variation and the mean of the urinary albumin to creatinine ratio fell in both groups at 52 weeks but both were significantly greater for the telmisartan compared to the losartan cohort. Mean systolic blood pressure reductions were not significantly different between groups at trial end. We conclude that telmisartan is superior to losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy, despite a similar reduction in blood pressure. In patients with diabetic nephropathy, lowering blood pressure and reducing proteinuria by over 30% correlates with a slower progression to kidney failure. We compared two different angiotensin receptor-blockers in a double blind, prospective trial of 860 patients with type 2 diabetes whose blood pressure levels was over 130/80 mmHg or who were receiving antihypertensive medication(s) and who had a morning spot urinary protein to creatinine ratio of 700 or more. Patients were randomized to telmisartan (a highly lipophilic agent with a long half-life) or losartan (with low lipophilicity and short half-life). The primary endpoint was the difference in the urinary albumin to creatinine ratio between the groups at 52 weeks. The geometric coefficient of variation and the mean of the urinary albumin to creatinine ratio fell in both groups at 52 weeks but both were significantly greater for the telmisartan compared to the losartan cohort. Mean systolic blood pressure reductions were not significantly different between groups at trial end. We conclude that telmisartan is superior to losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy, despite a similar reduction in blood pressure. Proteinuric kidney disease is a frequent complication of diabetes, the most common cause of kidney failure in the western world,1.US Renal Data System USRDS 2006 Annual Data Report: Atlas of End-Stage Renal Dieases in the United States. 2007 National Institutes of Health, National Institutes of Diabetes, DIgestive Diseases and Kidney Diseases2007www.usrds.orgGoogle Scholar and results in reduced life expectancy.2.Hillege H.L. Fidler V. Diercks G.F. et al.Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population.Circulation. 2002; 106: 1777-1782Crossref PubMed Scopus (1287) Google Scholar Post hoc analyses of renal outcome trials demonstrate that a >30% reduction in proteinuria at 6 months correlates with slowed progression of kidney disease.3.Bakris G. Clinical trials report. Proteinuria and blood pressure reduction: are they of equal importance to preserve kidney function?.Curr Hypertens Rep. 2005; 7: 357-358Crossref PubMed Google Scholar,4.Lea J. Greene T. Hebert L. et al.The relationship between magnitude of proteinuria reduction and risk of end-stage renal disease: results of the African American study of kidney disease and hypertension.Arch Intern Med. 2005; 165: 947-953Crossref PubMed Scopus (240) Google Scholar,5.de Z.D. Remuzzi G. Parving H.H. et al.Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL.Kidney Int. 2004; 65: 2309-2320Abstract Full Text Full Text PDF PubMed Scopus (762) Google Scholar,6.Nakao N. Seno H. Kasuga H. et al.Effects of combination treatment with losartan and trandolapril on office and ambulatory blood pressures in non-diabetic renal disease: a COOPERATE-ABP substudy.Am J Nephrol. 2004; 24: 543-548Crossref PubMed Scopus (37) Google Scholar Uncontrolled hypertension contributes to increases in proteinuria, and blood pressure control is associated with reduced urinary protein excretion and slowed decline in renal function.7.Sarafidis P.A. Khosla N. Bakris G.L. Antihypertensive therapy in the presence of proteinuria.Am J Kidney Dis. 2007; 49: 12-26Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar Achievement of a target blood pressure, that is, <130/80 mm Hg, in patients with proteinuria, using a blocker of the rennin–angiotensin system as part of the regimen, is recommended by current guidelines.8.Bakris G.L. Williams M. Dworkin L. et al.Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group.Am J Kidney Dis. 2000; 36: 646-661Abstract Full Text Full Text PDF PubMed Scopus (1203) Google Scholar,9.Chobanian A.V. Bakris G.L. Black H.R. et al.Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.Hypertension. 2003; 42: 1206-1252Crossref PubMed Scopus (9729) Google Scholar,10.Mancia G. De B.G. Dominiczak A. et al.2007 Guidelines for the Management of Arterial Hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).J Hypertens. 2007; 25: 1105-1187Crossref PubMed Scopus (4605) Google Scholar The current trial tests the hypothesis that a highly lipophilic11.Burnier M. Angiotensin II type 1 receptor blockers.Circulation. 2001; 103: 904-912Crossref PubMed Scopus (409) Google Scholar angiotensin-receptor blocker (ARB) with a long half-life will yield relatively greater antiproteinuric effects at similar levels of blood pressure control compared with one that has a shorter half-life and low lipophilicity. This prospective, randomized, double-blind, double-dummy, forced-titration, multicenter, parallel-group, study compared telMisartan (80 mg) vs losArtan (100 mg) in hypertensive type-2 DiabEtic patients with Overt nephropathy. It was conducted at 124 centers in Argentina, Australia, Brazil, Canada, Mexico, New Zealand, South Korea, Taiwan, Thailand, and the United States, with 1,567 outpatients meeting inclusion criteria and 860(55%) randomized to treatment (Table 1). There were many reasons for people not being randomized and most dealt with problems related to duration of follow-up and frequency of visits. Eighty percent of the total cohort completed the trial, 345 and 342 patients in the telmisartan and losartan groups, respectively. The mean duration of follow-up for the entire cohort was 324.25 days.Table 1Baseline characteristics of randomized AMADEO patients+All values are expressed as mean±s.d.Telmisartan 80-mg regimen (n=419)Losartan 100-mg regimen (n=441)Age (years)60.0±9.260.5±9.4<65 years (%)66.862.1Male (%)61.163.3Ethnicity (%)Caucasian44.949.2Black14.19.8Asian41.140.8Missing00.1Mean±s.d. BMI (kg/m2)30.1±6.8an=418.29.9±6.2bn=439.Current smokers (%)15.016.1Ex-smokers (%)38.739.8Duration of hypertension (years)9.0±8.9an=418.9.6±9.4bn=439.Duration of diabetic nephropathy (years)2.5±3.7cn=417.2.3±3.5dn=438.Duration of type-2 diabetes (years)14.6±8.414.1±8.1Urinary protein:creatinine (mg/g creatinine)++1970.9 (100.8%)en=413.2010.5 (104.5%)fn=437.Urinary albumin:creatinine (mg/g creatinine)++1400.8 (118.0%)gn=411.1387.0 (126.0%)hn=435.Urinary sodium:creatinine (mmol/g creatinine)++72.4 (95.1%)en=413.76.7 (88.4%)hn=435.Serum creatinine (mg/dl)++1.54 (40.6%)1.55 (41.2%)eGFR (ml/min/1.73 m2)49.5±21.649.6±22.4Serum aldosterone (ng/dl)++7.6 (91.9%)in=402.7.1 (90.8%)jn=428.C-reactive protein (mg/l)++2.2 (209.5%)an=418.2.4 (197.9%)bn=439.SBP (mm Hg)143.7±15.7143.2±15.4DBP (mm Hg)79.9±9.479.5±9.6Hemoglobin A1c (%)7.9±1.3gn=411.7.9±1.3hn=435.AMADEO, a prospective, randomized, double-blind, double-dummy, forced-titration, multicenter, parallel-group, 1-year treatment trial to compare telMisartan (80 mg) vs losArtan (100 mg) in hypertensive type-2 DiabEtic patients with Overt nephropathy; BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; gCV, geometric mean of variation; gMean, geometric mean; SBP, systolic blood pressure; s.d., standard deviation.+ All values are expressed as mean±s.d.a n=418.b n=439.c n=417.d n=438.e n=413.f n=437.g n=411.h n=435.i n=402.j n=428. Open table in a new tab AMADEO, a prospective, randomized, double-blind, double-dummy, forced-titration, multicenter, parallel-group, 1-year treatment trial to compare telMisartan (80 mg) vs losArtan (100 mg) in hypertensive type-2 DiabEtic patients with Overt nephropathy; BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; gCV, geometric mean of variation; gMean, geometric mean; SBP, systolic blood pressure; s.d., standard deviation. Although each agent reduced adjusted mean urinary protein-to-creatinine (UPC) significantly (29.8% telmisartan (P<0.0001) and 21.4% losartan (P<0.0001)), the reduction in UPC from baseline was greater for telmisartan (P=0.03; Figure 1), thus achieving the primary endpoint. Table 2 summarizes secondary endpoints. In the telmisartan group, the geometric mean urinary albumin:creatinine was reduced from 1426.1 mg/g to 952.5 mg/g creatinine (P<0.0001). In the losartan group, the corresponding values for baseline and end of treatment were 1,390.5 and 1,054.9 mg/g creatinine (P 5.5 mEq/l. There were six discontinuations in each group due to treatment-related adverse events. During the study, 25 patients died, but no death was considered study drug-related. The results of this trial demonstrate that in patients with hypertension and diabetic nephropathy, a telmisartan-based regimen is superior to a losartan-based regimen for reducing proteinuria, given similar levels of blood pressure reduction at 1 year. This change in proteinuria was based on a change in spot urine protein:creatinine. This method overcomes the drawbacks of 24-h urine collection12.Ruggenenti P. Gaspari F. Perna A. et al.Cross sectional longitudinal study of spot morning urine protein:creatinine ratio, 24 h urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes.BMJ. 1998; 316: 504-509Crossref PubMed Google Scholar and correlates with such values in different patient groups;13.Ruggenenti P. Gaspari F. Perna A. et al.Cross sectional longitudinal study of spot morning urine protein:creatinine ratio, 24 h urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes.BMJ. 1998; 316: 504-509Crossref PubMed Scopus (206) Google Scholar,14.Rodby R.A. Rohde R.D. Sharon Z. et al.The urine protein to creatinine ratio as a predictor of 24-h urine protein excretion in type 1 diabetic patients with nephropathy. the Collaborative Study Group.Am J Kidney Dis. 1995; 26: 904-909Abstract Full Text PDF PubMed Scopus (101) Google Scholar thus, it is a recommended method for clinical trials.15.K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease.Am J Kidney Dis. 2004; 43: 1-290PubMed Google Scholar,16.Bakris G.L. Microalbuminuria: Marker of Kidney and Cardiovascular Disease. 1st edn. Current Medicine Group, London2007Google Scholar There are many factors that affect proteinuria and may have influenced the results, although most of those did not account for differences seen in this trial. One possible factor that could have affected proteinuria is a disproportionate increase in dietary sodium intake in one group, since this is known to blunt the antiproteinuric effects of the renin–angiotensin system blockers.17.Jones-Burton C. Mishra S.I. Fink J.C. et al.An in-depth review of the evidence linking dietary salt intake and progression of chronic kidney disease.Am J Nephrol. 2006; 26: 268-275Crossref PubMed Scopus (85) Google Scholar However, we detected no differences between groups in sodium excretion as assessed by spot urinary sodium:creatinine ratio at any time point where proteinuria was assessed. Thus, in this study, changes in proteinuria cannot be attributed to differences in dietary sodium. Another possible explanation for these between-group differences in proteinuria could relate to a lower blood pressure favoring one group. Differences in diastolic blood pressure were not present at any time during the trial. A trend for a lower systolic pressure, however, was present in the telmisartan group early in the trial, but failed to reach significance at trial end. Moreover, the greatest difference in systolic blood pressure was noted on day 56, where the difference between groups was 2.9 mm Hg. At every other time point, non-significant differences of 5.5 mEq/l between groups was 1.8% for the study overall, with no difference between groups. Thus, both telmisartan and losartan were relatively well tolerated and safe. It, therefore, appears that there is no clear explanation for these proteinuria differences. Losartan has approval by the Food and Drug Administration for slowing diabetic nephropathy, based on the results of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study.23.Brenner B.M. Cooper M.E. de Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (4533) Google Scholar In the RENAAL study, proteinuria was reduced by 29% at 6 months and correlated with significant slowing of nephropathy progression compared with placebo.24.de Z.D. Remuzzi G. Parving H.H. et al.Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL.Kidney Int. 2004; 65: 2309-2320Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar Moreover, post hoc analysis of the RENAAL trial showed that losartan-induced changes in proteinuria were more predictive of renal outcomes than blood pressure changes.25.Eijkelkamp W.B. Zhang Z. Remuzzi G. et al.Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial.J Am Soc Nephrol. 2007; 18: 1540-1546Crossref PubMed Scopus (270) Google Scholar In this study, the proteinuria reduction observed with the losartan regimen was 21.4 vs 29.8% with a telmisartan regimen. In both treatment groups, the greatest reduction in proteinuria was apparent during the first 26 weeks and persisted for the remainder of the trial. Similar trends were also observed for albuminuria. In a separate study, the rate of progression from micro- to macro-albuminuria in patients with type-2 diabetes was reduced by telmisartan.26.Makino H. Haneda M. Babazono T. et al.Prevention of transition from incipient to overt nephropathy with telmisartan in patients with type 2 diabetes.Diabetes Care. 2007; 30: 1577-1578Crossref PubMed Scopus (179) Google Scholar This anti-albuminuric effect of telmisartan was independent of blood pressure level, as transition rates were reduced in both hypertensive (>140/90 mm Hg) and normotensive patients. We conclude that a telmisartan-based regimen for blood pressure reduction provides robust antiproteinuric effect in hypertensive patients with nephropathy-associated type-2 diabetes. This antiproteinuric effect is greater than a losartan-based regimen at levels of blood pressure that were not different. Based on available trial data, this difference in antiproteinuric effect may translate into better renal and cardiovascular outcomes. Long-term outcome studies, such as ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), will demonstrate whether the antiproteinuric effect of telmisartan is associated with a reduction in cardiovascular events in high-risk patients.27.Teo K. Yusuf S. Sleight P. et al.Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials.Am Heart J. 2004; 148: 52-61Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar This is a prospective, randomized, double-blind, double-dummy, forced-titration, multicenter, parallel-group study. After a 4-week placebo washout period, with discontinuation of any ARB, angiotensin-converting enzyme inhibitor, or direct vasodilator, eligible patients were randomized to telmisartan or losartan treatment. During the first 2 weeks, the once-daily dose of telmisartan was 40 mg and 50 mg for losartan. For the remaining 50 weeks, the doses of telmisartan and losartan were 80 and 100 mg/day, respectively. Additional antihypertensive medication (excluding other ARBs, angiotensin-converting enzyme inhibitors, or direct vasodilators) could be given following forced titration to achieve the blood pressure targets ( 35% increase in serum creatinine during the washout period or serum potassium level >5 mEq/l; (3) non-diabetic renal disease; (4) clinically significant heart disease, stroke, renal artery stenosis, hepatic dysfunction, or electrolyte imbalance; (5) known hypersensitivity to any component of the study medications; and (6) requiring chronic immunosuppressive therapy. The primary efficacy endpoint was change from baseline in early-morning spot UPC. Secondary renal endpoints included change from baseline in early-morning spot albumin:creatinine; estimated glomerular filtration rate, using the modified MDRD equation;28.Levey A.S. Coresh J. Greene T. et al.Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate.Ann Intern Med. 2006; 145: 247-254Crossref PubMed Scopus (3696) Google Scholar and early-morning spot sodium:creatinine. Also, a composite of a doubling of serum creatinine concentration, end-stage renal disease (need for long-term dialysis, renal transplantation, or a serum creatinine ≥6 mg/dl), or death was assessed. Other secondary endpoints were change from baseline in systolic blood pressure and diastolic blood pressure, high-sensitivity C-reactive protein, and serum aldosterone. Adverse events and safety laboratories were also monitored. All samples were stored at –20 °C and dispatched to a central laboratory (Quest Diagnostics Clinical Trials, Van Nuys, CA, USA) for analysis. The power of the study was assessed assuming a standard deviation of the change from baseline in UPC from similar cohorts observed in different trials, and expected to be approximately 2 mg/g creatinine.29.Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar,30.Brenner B.M. Cooper M.E. de Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar Thus, 340 patients per treatment arm would yield 90% power at the 5% (two-sided) level of significance to detect a between group difference of 0.5 mg/g creatinine in UPC in the reduction from baseline. We further assumed, however, a 15% dropout rate with no final UPC measurement; consequently, 400 patients per treatment arm were required to identify any differences in efficacy. Efficacy was determined in patients with a baseline and ≥1 on-treatment renal efficacy parameter measurement, with last observation carried forward. For the primary endpoint, an analysis of covariance that included treatment and pooled center as class effects, with baseline as a covariate, was performed on the log-transformed data. Mean values were expressed as geometric means (geometric coefficient of variation, %). Significance of changes from baseline within treatment groups and differences between treatment groups were established by two-sided 95% confidence interval and P-value. The same procedure was used for all secondary renal endpoints other than estimated glomerular filtration rate, which were expressed as arithmetic mean and standard deviation. Changes in blood pressure were expressed as mean values and standard error. Time-to-event data were analyzed by Kaplan–Meier method, with treatment groups being compared by means of log-rank test. Baseline demographics were summarized descriptively for each treatment. All the authors declared no competing interests. Investigators Argentina: Mario Bendersky, Betina Bustos, Betina, Alberto Caccavo, Emilo Kuschnir, Jorge Lowenstein, Silvia Nicolai, Ernesto Paolasso, Siliva Saavedra, Ramiro Sanchez, Jorge Thierer. Australia: William Jeffries, Garry Jennings, Jeff Karrasch; Brazil: Fernando Almeida, João Felício, Adriana Forti, Roberto Franco, Rosângela Milagres, Rogério Paula, Artur Ribeiro, José Saraiva; Canada: Ronnie Aronson, Gordon Bailey, Paul Barré, Sabyasachi Bose, Ellen Burgess, Richard Dumas, Jean-Marie Ekoe, Thomas Elliott, Richard Goluch, Irving Gottesman, Sita Gourishankar, Jean-Pierre Halle, Gavril Hercz, Shivinder Jolly, Phillip McFarlane, Theodore Monchesky, Liam Murphy, Tewfik Nawar, Malvinder Parmar, Robert Petrella, Stuart Ross, Luis Salgado, Robert Schlosser, Jay Silverberg, Steven Soroka, Hugh Tildesley, Yaw Twum-Barima, Deborah Zimmerman; Mexico: Ernesto Cardona, Jaime Illescas, Norberto Matadamas, Eduardo Meaney, José Parra, Rogelio Peralta, Jesús Rivera, Ignacio Rodriguez, Jorge Torres Gutierrez, Sergio Trevethan; New Zealand: Ajith Dissanayake, Russell Scott; South Korea: Chul Woo Ahn, Hye-Soon Kim, Young Duk Song. Taiwan: Chien-Wen Chou, Shinn-Tzon Gong, Tien-Shang Huang, Yi-Jen Hung, Tin-Kwang Lin, Ji-Hung Wang; Thailand: Ampica Mangklabruks, Thongchai Pratipanawatr, Nopawan Kittivat, Prasart Laothavorn, Peera Buranakitjaroen, Suthon Porntisan; USA: Spiros Arbes, Habib Azad, George L Bakris, Thomas Berl, DeAnna E Cheek, Jhoong Cheigh, William H Cleveland, Debbie Cohen, Dalila B Corry, Troy E Dixon, Steven Fishbane, Linda Fried, Francis Gabbai, Leland E Garrett Jr, Michael Germain, Jesse Mark Goldman, Stephen Graham, Syed A Hussain, Kambiz Kalantarinia, Mark S Kipnes, Michael Krishnan, Cheryl Laffer, Sam Lerman, Barton Levine, Harold R Locay, Rafael A Lopez, Laura Lyngby Mulloy, Leonard G Meggs, James H Mersey, Sylvia D Noble, Ernesto Perez, Pablo E Pergola, Velvie Anne Pogue, German Ramirez, Philip Raskin, Efrain Reisin, Paul D Schneider, Steven Schwartz, Craig A Shadur, Mary Jo Shaver, Harmeet Singh, Richard Solomon, Bruce S Spinowitz, Chao Sun, Vinay A Sunku, Manuel Velasques, Donald G Vidt, Cristovao Vieira, Mark Williams, Bessie A Young, Steven Zeig.