Citation for published version (APA): Eijkelkamp, W. B. A. (2007). Reversing the reno-cardiac perspective s.n.

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1 University of Groningen Reversing the reno-cardiac perspective Eijkelkamp, Wouter Bernardus Alfons IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2007 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Eijkelkamp, W. B. A. (2007). Reversing the reno-cardiac perspective s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Chapter II Renal Function and Risk for Cardiovascular Events in Type 2 Diabetic Patients with Hypertension: the RENAAL and LIFE Studies Wouter B.A. Eijkelkamp 1, Zhongxin Zhang 2, Barry M. Brenner 3, Mark E. Cooper 4, Richard B. Devereux 5, Björn Dahlöf 6, Hans Ibsen 7, William F. Keane 2, Lars H. Lindholm 8, Michael H. Olsen 7, Hans-Henrik Parving 9, Giuseppe Remuzzi 10, Shahnaz Shahinfar 2, Steven M. Snapinn 2, Kristian Wachtell 11 and Dick de Zeeuw 1 1 Department of Clinical Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 2 Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, New Jersey, USA; 3 Department of Medicine, Renal Division, Brigham and Women s Hospital and Harvard School of Medicine, Boston, Massachusetts, USA; 4 Baker Medical Research Institute, Melbourne, Australia; 5 Weill Medical College of Cornell University, New York, New York; 6 Department of Medicine, Sahlgrenska Hospital/Östra, Gothenburg, Sweden; 7 Department of Internal Medicine, Glostrup University Hospital, Glostrup, Denmark; 8 Public Health and Clinical Medicine, Umeå University Hospital, Umeå, Sweden; 9 Steno Diabetes Center, Gentofte, and Faculty of Health Science, Aarhus University, Denmark; 10 Mario Negri Institute for Pharmacological Research, Bergamo, Italy; 11 Department of Cardiology, Rigshospitalet, Copenhagen, Denmark. Journal of Hypertension Apr; 25(4):

3 Abstract To investigate whether a threshold exists for cardiovascular risk in type 2 diabetic patients with hypertension, the association between renal function and cardiovascular risk was examined across the entire physiological range of serum creatinine. The RENAAL and LIFE studies enrolled 1513 and 1195 patients with type 2 diabetes and hypertension, respectively. The relationship between baseline serum creatinine and the risk for a composite outcome of myocardial infarction, stroke or cardiovascular death was examined using Cox regression models. To adjust for heterogeneity between studies and treatment groups, these factors were included as strata when applicable. The analyses were conducted with adjustment for age, gender, smoking, alcohol use, blood pressure, heart rate, total and high-density lipoprotein (HDL) cholesterol, hemoglobin, albuminuria and prior cardiovascular disease. The hazard ratios across the baseline serum creatinine categories <0.9 mg/dl, mg/dl, mg/dl, mg/dl and 2.8 mg/dl were 0.51 (95% confidence interval 0.34, 0.74), 0.74 (0.55, 1.00), 1.00 (reference), 1.24 (0.96, 1.59) and 1.67 (1.17, 2.91), respectively. Baseline serum creatinine (per mg/dl) strongly predicted the composite cardiovascular endpoint in LIFE [2.82 (1.74, 4.56), P < 0.001], RENAAL [1.41 (1.12, 1.79), P < 0.001], as well as the combined studies [1.51 (1.21, 1.87), P < 0.001]. We conclude that a progressively higher risk for the composite cardiovascular endpoint was shown with incremental baseline serum creatinine in type 2 diabetic patients with hypertension, even within the normal range. Thus, there appears to be no serum creatinine threshold level for an increased cardiovascular risk. Baseline serum creatinine was a major independent risk factor for cardiovascular disease. Key words Angiotensin II receptor blocker, cardiovascular outcome, hypertension, intervention, renal function, serum creatinine, type 2 diabetes. 10

4 Introduction Type 2 diabetes is an important risk factor for cardiovascular disease, and previous studies have shown that concurrent renal impairment increases this cardiovascular risk 1-7. However, current data in type 2 diabetes mostly disregard the frequently observed concomitant presence of hypertension in these patients, or only relate to diabetic patients with moderate to severe renal function loss. Patients with relatively normal renal function, as well as those with severe renal impairment including dialysis, have been routinely excluded from pharmacological intervention studies aimed at documenting cardiovascular risk reduction in diabetic patients. The current analysis was designed to investigate the risk for cardiovascular morbidity and mortality in type 2 diabetic patients with hypertension across all stages of renal function, including patients with apparently normal renal function. This was achieved by analyses of cardiovascular outcomes in diabetic patients with hypertension from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) and Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) studies, cohorts that had different but overlapping renal function ranges at baseline and a sufficiently long follow-up period. In addition, the relative importance of incremental renal function impairment among other traditional risk factors for cardiovascular disease could be investigated within this large set of diabetic patients with hypertension. 11

5 Materials and Methods LIFE study design. The LIFE study was a double-blind, randomized, parallel-group study designed to compare the efficacy of losartan- with atenolol-based regimens in the reduction of cardiovascular morbidity and mortality in patients with hypertension and electrocardiographic left ventricular hypertrophy 8. The primary endpoint was the composite endpoint of cardiovascular death, stroke and myocardial infarction. The LIFE study included 1195 patients with type 2 diabetes and hypertension at baseline. Patients were given placebo for 1-2 weeks after which they were assigned to treatment with either losartan 50 mg or atenolol 50 mg once daily (o.d.) if they had sitting systolic blood pressure (SBP) of mmhg, diastolic blood pressure (DBP) of mmhg, or both. In both groups, hydrochlorothiazide 12.5 mg was added in case of insufficient blood pressure control at the next study visit, i.e. SBP 140 mmhg or DBP 90 mmhg. The losartan or atenolol dosage was increased to 100 mg o.d., then hydrochlorothiazide increased to 25 mg o.d., and other non-beta-blocker/angiotensin converting enzyme inhibitor/angiotensin II receptor blocker antihypertensive medications were added in order to reach target trough blood pressure of <140/90 mmhg. Further information on the complete study protocol, clinical measures, demographics and the main outcome is available in various publications RENAAL study design. The RENAAL study was a double-blind, randomized, placebocontrolled study designed to evaluate the renoprotective effects of losartan in patients with type 2 diabetes and nephropathy 11. Myocardial infarction, stroke and cardiovascular death were prespecified secondary endpoints in RENAAL. A total of 1513 patients with type 2 diabetes were included in the RENAAL study. During the 6- week screening phase, patients continued to receive their standard antihypertensive therapy. If they had been taking an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, these medications were discontinued and replaced by alternative open-label antihypertensive medications such as diuretics, calcium-channel antagonists or beta-blockers. Patients were randomly assigned to receive either losartan 50 mg or placebo o.d. along with conventional antihypertensive therapy, with possible subsequent dose increase to losartan 100 mg o.d. or placebo-equivalent dose if the trough blood pressure was above the target of 140/90 mmhg. More detailed information on the study protocol and the main study outcome has been presented elsewhere 11;12. 12

6 Statistical analysis a In this post-hoc analysis, the risk for the composite endpoint of myocardial infarction, stroke or cardiovascular death was explored in relationship to baseline serum creatinine. Event rates, hazard ratios (HR) and 95% confidence intervals (CI) were calculated for the individual and combined studies for the following categories of baseline serum creatinine: <0.9 mg/dl, mg/dl, mg/dl (reference group), mg/dl and 2.8 mg/dl. The serum creatinine categories were chosen post hoc, with the aim of providing easily understandable thresholds with sufficient sample sizes and number of events for each category. The event rate per 1000 patient-years of follow-up was determined by the time-to-endpoint date, death date, lost-to-follow-up date, or end-ofstudy cut-off date, whichever occurred first. Cox regression models were used with the serum creatinine categories as covariates, and study and treatment group as strata, as needed, to adjust for heterogeneity between studies and treatment groups. The analysis was conducted with adjustment for age, gender, smoking, alcohol use, systolic and diastolic blood pressures, pulse rate, total and high-density lipoprotein (HDL) cholesterol, hemoglobin, albuminuria and history of prior cardiovascular disease (ischemic heart disease, peripheral vascular disease and stroke/transient ischemic attack) using the backward selection method and an alpha of To investigate whether results were borne out by all individual components of the composite cardiovascular endpoint (i.e. fatal and non-fatal stroke, fatal and non-fatal myocardial infarction, and cardiovascular death), we performed similar analyses with dichotomous stratification for the level of baseline serum creatinine on each individual cardiovascular endpoint. To show whether serum creatinine was an independent risk factor, a similar multivariate Cox regression model was conducted with serum creatinine as the continuous variable. All statistical analyses were performed using SAS version 8 (SAS Institute Inc., Cary, North Carolina, USA). 13

7 Results The LIFE diabetic population with hypertension consisted of 1195 patients (mean age 67.4 years) and the serum creatinine level at baseline was 1.8 mg/dl. The RENAAL study included 1513 diabetic patients (mean age 60.2 years) with a baseline serum creatinine level between 1.0 and 3.0 mg/dl. Baseline demographics, vital signs, medical history and laboratory results for diabetic patients in the LIFE, RENAAL and combined studies are presented in Table 1. In the LIFE population, a larger proportion was female and all patients had left ventricular hypertrophy. The LIFE patients also had higher mean age and baseline blood pressure. The RENAAL patients had higher serum creatinine and urine albumin/creatinine ratio. A total of 48 of 1195 diabetic LIFE patients had no value for serum creatinine at baseline and thus were excluded from the present analysis. There were no missing values for baseline serum creatinine in the RENAAL population. The mean follow-up durations in the LIFE and RENAAL populations were 4.7 and 3.4 years, respectively. Event rates for the composite cardiovascular endpoint in the LIFE, RENAAL and combined diabetic populations were 45, 68 and 56 per 1000 patient-years of follow-up, respectively. Among the evaluated risk markers for the composite endpoint, baseline serum creatinine (per mg/dl) was a major cardiovascular risk factor in LIFE (HR = 2.82, 95% CI 1.74, 4.56; P < 0.001), RENAAL (1.41, 95% CI 1.12, 1.79; P < 0.001), as well as the combined studies (1.51, 95% CI 1.21,1.87; P < 0.001) (Table 2). The event rates and HRs per baseline serum creatinine category for the LIFE, RENAAL and combined studies are presented in Table 3, showing a higher cardiovascular risk with incremental baseline serum creatinine. Similar results were obtained when the data were analyzed on the basis of categorized estimated glomerular filtration rate (egfr) and when separately analyzed by treatment administered (data not shown). There was no apparent interaction between treatment allocation and serum creatinine. The Kaplan- Meier curves for the composite cardiovascular endpoint in relationship to serum creatinine strata are presented in Figure 1. The analysis of the components of the combined cardiovascular endpoint showed that all individual endpoints contributed to the overall effect observed, as reflected in consistently increased HRs for individual events in patients with higher baseline serum creatinine (data not shown). 14

8 Table 1. Baseline characteristics in the LIFE, RENAAL R and combined studies LIFE RENAAL Combined n = 1195 n = 1513 n = 2708 Age (years) 67.4 (7.0) 60.2 (7.4) 63.4 (8.1) Female gender 634 (53.1) 557 (36.8) 1191 (44.0) Race White 1025 (85.8) 735 (48.6) 1760 (65.0) Black 133 (11.1) 230 (15.2) 363 (13.4) Hispanic 25 (2.1) 277 (18.3) 302 (11.2) Asian 10 (0.8) 252 (16.7) 262 (9.7) Systolic blood pressure (mmhg) (14.0) (19.3) (20.9) Diastolic blood pressure (mmhg) 96.2 (9.6) 82.4 (10.4) 88.5 (12.2) Pulse rate (beats/min) 76.0 (11.6) 75.1 (10.2) 75.5 (10.8) Framingham risk score 30.7 (8.4) 14.6 (8.5) 22.0 (11.7) Cornell-voltage product (mv ms) a (977.9) (781.1) (1126.3) Sokolow-Lyon (mv) a 28.6 (10.2) 22.6 (8.4) 25.3 (9.7) Current smoking 594 (49.8) 273 (18.1) 867 (32.1) Medical history Angina/ischemic heart disease 465 (38.9) 630 (41.6) 1095 (40.4) Arrhythmia/atrial fibrillation 195 (16.3) 155 (10.2) 350 (12.9) Heart failure 48 (4.0) 82 (5.4) 130 (4.8) Left ventricular hypertrophy a 1195 (100) 187 (13.1) 1382 (52.7) Myocardial infarction 103 (8.6) 163 (10.8) 266 (9.8) Peripheral vascular disease 89 (7.4) 188 (12.4) 277 (10.2) Stroke/transient ischemic attack 287 (24.0) 315 (20.8) 602 (22.2) Laboratory parameters Serum creatinine (mg/dl) 1.0 (0.2) 1.9 (0.5) 1.5 (0.6) Estimated GFR (ml/min) 70.2 (15.3) 39.8 (12.3) 52.9 (20.4) Hemoglobin (mg/dl) 14.3 (1.3) 12.5 (1.8) 13.2 (1.9) Total cholesterol (mg/dl) (44.0) (55.5) (50.9) HDL cholesterol (mg/dl) 50.6 (14.4) 45.1 (15.1) 47.4 (15.0) Urine albumin/creatinine ratio (mg/g) b 27.0 (8.6, 106.6) (558.0, ) (45.0, ) GFR, glomerular filtration rate. Data are n (%) or mean (SD). a Left ventricular hypertrophy was an enrollment criterion for LIFE: Cornell product >2440 mv ms and/or Sokolow-Lyon >38 mv. b Median value with the 25th and 75th percentiles. Nephropathy was an enrollment criterion for RENAAL: urine albumin/creatinine ratio 300 mg/g and serum creatinine mg/dl ( for males weighing >60 kg). 15

9 Table 2. Multivariate analysis for composite endpoint of myocardial infarction, stroke or cardiovascular death in LIFE, RENAAL and combined studies HR (95% CI) Chi-squared P value LIFE Serum creatinine (per 1 mg/dl) 2.82 (1.74, 4.56) 17.9 <0.001 Age (per 10 years) 1.53 (1.26, 1.87) 17.8 <0.001 Stroke/transient ischemic attack 1.93 (1.38, 2.70) 15.0 <0.001 Peripheral vascular disease 2.18 (1.47, 3.24) 14.9 <0.001 Albuminuria (per g/g) 1.32 (1.13, 1.54) 12.5 <0.001 RENAAL Stroke/transient ischemic attack 2.01 (1.49, 2.72) 21.1 <0.001 Peripheral vascular disease 1.62 (1.21, 2.17) Ischemic heart disease 1.47 (1.16, 1.85) Serum creatinine (per mg/dl) 1.41 (1.12, 1.79) Albuminuria (per g/g) 1.09 (1.03, 1.17) Combined Stroke/transient ischemic attack 1.96 (1.57, 2.45) 34.8 <0.001 Age (per 10 years) 1.37 (1.20, 1.56) 22.8 <0.001 Albuminuria (per g/g) 1.14 (1.08, 1.21) 19.0 <0.001 Peripheral vascular disease 1.66 (1.31, 2.11) 17.1 <0.001 Serum creatinine (per mg/dl) 1.51 (1.21, 1.87) 14.0 <0.001 Ischemic heart disease 1.39 (1.15, 1.67) 12.1 <0.001 Smoking 1.33 (1.09, 1.63) HDL cholesterol (per 10 mg/dl) 0.92 (0.86, 0.98) CI, confidence interval; HDL, high-density lipoprotein; HR, hazard ratio. The multivariate Cox model was performed with the following risk markers as covariates: age, gender, smoking, alcohol use, systolic and diastolic blood pressure, pulse rate, total and HDL cholesterol, hemoglobin, serum creatinine, albuminuria and history of prior cardiovascular disease. Analysis adjusted by treatment group and study as needed as strata. A backward selection method was used with alpha =

10 Table 3. Analysis of composite endpoint of myocardial infarction, stroke or CV death by baseline serum creatinine in LIFE, RENAAL and combined studies Baseline scr (mg/dl) LIFE K (Rate) HR (95% CI) < (29.4) 0.48 (0.32, 0.72)*** (45.3) 0.71 (0.51, 0.99)* (67.0) 1.00 (reference) (95.1) 1.23 (0.65, 2.32) 2.8 Baseline scr (mg/dl) RENAAL K (Rate) HR (95% CI) < (50.8) 0.95 (0.44, 2.07) (53.4) 1.00 (reference) (72.3) 1.37 (1.04, 1.79)* (123.4) 2.24 (1.42, 3.54)** Baseline scr (mg/dl) Combined n K (Rate) HR (95% CI) < (29.3) 0.51 (0.34, 0.74)*** (45.6) 0.74 (0.55, 1.00)* (58.7) 1.00 (reference) (73.4) 1.24 (0.96, 1.59) (123.4) 1.84 (1.17, 2.91)** * P < 0.05; **P < 0.01; ***P < scr, serum creatinine; CI, confidence interval; K (Rate), number of events (event rate per 1000 patient-years of follow-up). HR (95% CI), hazard ratio relative to mg/dl adjusted for baseline covariates age, sex, smoking, alcohol use, sitting diastolic pressure, sitting systolic pressure, pulse rate, total cholesterol, high-density lipoprotein (HDL) cholesterol, hemoglobin, albuminuria and history of prior cardiovascular disease. Analysis adjusted by treatment group and study as needed as strata. Backward selection method was used with alpha =

11 Figure 1. Three-year Kaplan-Meier curve of the percentage of patients with the composite endpoint of myocardial infarction, stroke or cardiovascular death in the combined studies, stratified by baseline serum creatinine. 18

12 Discussion Type 2 diabetes is emerging as a major health problem and tends to cluster with hypertension in individual subjects. To our knowledge, this is the first analysis describing the risk for cardiovascular events in type 2 diabetic patients with hypertension across all stages of renal function. A progressively higher risk for the composite endpoint of myocardial infarction, stroke and cardiovascular death was observed with incremental serum creatinine in type 2 diabetic patients with hypertension in LIFE and RENAAL as well as the combined studies. Each individual endpoint contained in the composite cardiovascular outcome measure contributed to the overall effect observed. Interestingly, increased cardiovascular risk already appeared to evolve from a normal serum creatinine range of mg/dl compared with values <0.9 mg/dl (Table 3 and Figure 1). Thus, there appears to be no serum creatinine threshold level for an increased cardiovascular risk. The results of the present analysis complement previously obtained data in patients with hypertension only and in subjects derived from the general population 13;14. These studies also showed an independent and graded association between increasing renal impairment and the rates of cardiovascular morbidity and mortality. Altogether, these data establish renal impairment as a key risk factor for cardiovascular complications across important patient populations. Among the evaluated risk markers for the composite endpoint, baseline serum creatinine was a major cardiovascular risk factor in LIFE, RENAAL and the combined studies (Table 2). This applied to the level of albuminuria as well, which appeared to have a predictive value rather comparable to serum creatinine across these studies (see Chi-squared statistics). Pre-existent cardiovascular morbidity, as evidenced by the presence of cerebral vascular disease, peripheral vascular disease or ischemic heart disease, also showed a strong association with the composite cardiovascular endpoint across these studies. This was not observed for either systolic or diastolic pressure, which may be related to the substantial proportion of patients with pre-existent cardiovascular disease at baseline predicting recurrent cardiovascular events more strongly than blood pressure. Also, the design of both studies (blood pressuredependent uptitration) mandated that blood pressure was controlled to a common target level in all patients during these studies, which may further limit the role of baseline blood pressure as a strong predictor for the cardiovascular outcomes. The mechanism underlying this independently increased risk in patients with increasing renal impairment is not completely understood, but multiple explanations exist for the association between chronic kidney disease and subsequent cardiovascular 19

13 morbidity and mortality. Various studies have indicated that impaired renal function is associated with increased levels of inflammatory factors, left ventricular hypertrophy, abnormal apolipoprotein levels, elevated plasma homocysteine, enhanced coagulability, anemia, increased arterial calcification, endothelial dysfunction, arterial stiffness and renin-angiotensin-system activation The way these and other factors may interact to increase the risk of adverse cardiovascular outcomes remains unclear at present, but finding the underlying mechanism would constitute a major advance in the quest for more effective, targeted treatment of patients at risk. The fact that both myocardial infarction and stroke contributed to the overall composite outcome point towards generalized vascular pathophysiological mechanisms driven or influenced by the extent of renal function loss. In this respect, it is important to emphasize that intervention in the renin angiotensin system can improve cardiovascular and renal outcomes in type 2 diabetic patients with hypertension 23, which may be particularly relevant for those with more severe renal impairment 24. A limitation of the last part of the analyses in which both studies were combined concerns the partially different populations across these studies. Although both studies enrolled a large population of type 2 diabetic patients with hypertension, the RENAAL study enrolled patients with concomitant nephropathy, while left ventricular hypertrophy was the main co-morbid condition in the LIFE study. This distinction in eligibility criteria, however, does not appear to compromise the results. Both populations appear to have similar cardiovascular event rates when compared at the same baseline serum creatinine level. Indeed, the analyses showed comparable hazard ratios in the overlapping range of renal function of both individual studies, indicating that a comparable cardiovascular risk is present at each stage of renal function, regardless of other co-morbid conditions in type 2 diabetic patients with hypertension (Table 3). In agreement with this, baseline renal function was a major risk factor for cardiovascular complications across these studies among a comprehensive set of predictor variables including prior cardiovascular disease, age, albuminuria, smoking and others. 20

14 Conclusion These outcomes analyses of the LIFE and RENAAL studies showed a progressively increasing risk for cardiovascular complications across the entire range of incremental baseline serum creatinine, with serum creatinine as a major independent risk factor for cardiovascular morbidity and mortality in type 2 diabetic patients with hypertension. An increased cardiovascular event rate was already present within the normal serum creatinine range at values of mg/dl, suggesting no serum creatinine threshold level for an increased cardiovascular risk. The findings highlight the clinical value of serum creatinine measurements to assess both renal and cardiovascular risk. An effective pharmacological preservation of renal function would serve to accomplish a composite goal of reducing the increasing number of type 2 diabetic patients with hypertension progressing to end-stage renal disease and associated cardiovascular morbidity

15 Acknowledgements The authors acknowledge Ms Paulette A. Lyle for assistance with preparation of the manuscript. The authors further acknowledge the tremendous supportive role of all investigators, support staff and participating patients in the LIFE and RENAAL studies. The LIFE and RENAAL studies were sponsored by Merck & Co., Inc. Drs Brenner, Cooper, de Zeeuw, Keane, Parving and Remuzzi (members of the RENAAL Steering Committee); Drs Dahlof, Devereux, Ibsen and Lindholm (members of the LIFE Steering Committee); and Drs Olsen and Wachtell (LIFE investigators) have received grant support from Merck. Drs Keane, Shahinfar, Snapinn and Zhang are, or have been, employees of Merck and may own stock or hold stock options in the company. 22

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