Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials (original) (raw)

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1

Department of Clinical Pharmacology

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University Medical Center Groningen, University of Groningen

,

Antonius Deusinglaan 1, 9713 AV Groningen

,

The Netherlands

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1

Department of Clinical Pharmacology

,

University Medical Center Groningen, University of Groningen

,

Antonius Deusinglaan 1, 9713 AV Groningen

,

The Netherlands

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1

Department of Clinical Pharmacology

,

University Medical Center Groningen, University of Groningen

,

Antonius Deusinglaan 1, 9713 AV Groningen

,

The Netherlands

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1

Department of Clinical Pharmacology

,

University Medical Center Groningen, University of Groningen

,

Antonius Deusinglaan 1, 9713 AV Groningen

,

The Netherlands

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2

University of Colorado Medical School

,

Denver, CO

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USA

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3

Mario Negri Institute for Pharmacological Research

,

Bergamo

,

Italy

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4

Melbourne Renal Research Group

,

Royal Melbourne Hospital

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Melbourne

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Australia

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5

Vanderbilt University School of Medicine, Department of Nephrology

,

Nashville, TN

,

USA

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6

Department of Medical Endocrinology

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University Hospital of Copenhagen

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Copenhagen

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Denmark

7

Department of Health Science

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Aarhus University

,

Aarhus

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Denmark

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Hiddo J. Lambers Heerspink*

1

Department of Clinical Pharmacology

,

University Medical Center Groningen, University of Groningen

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Antonius Deusinglaan 1, 9713 AV Groningen

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The Netherlands

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Revision received:

28 December 2010

Accepted:

21 January 2011

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Frank A. Holtkamp, Dick de Zeeuw, Pieter A. de Graeff, Gozewijn D. Laverman, Tom Berl, Giuseppe Remuzzi, David Packham, Julia B. Lewis, Hans-Henrik Parving, Hiddo J. Lambers Heerspink, Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy_:_ a post hoc analysis of the combined RENAAL and IDNT trials, European Heart Journal, Volume 32, Issue 12, June 2011, Pages 1493–1499, https://doi.org/10.1093/eurheartj/ehr017
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Abstract

Aims

The long-term cardioprotective effect of angiotensin receptor blockers (ARBs) is associated with the short-term lowering of its primary target blood pressure, but also with the lowering of albuminuria. Since the individual blood pressure and albuminuria response to an ARB varies between and within an individual, we tested whether the variability and discordance in systolic blood pressure (SBP) and albuminuria response to ARB therapy are associated with its long-term effect on cardiovascular outcomes.

Methods and results

The combined data of the RENAAL and IDNT trials were used. We first investigated the extent of variability and discordance in SBP and albuminuria response (baseline to 6 months). Subsequently, we assessed the combined impact of residual Month 6 SBP and albuminuria level with cardiovascular outcome. In ARB-treated patients, 421 patients (34.5%) either had a reduction in SBP but no reduction in albuminuria, or vice versa, indicating substantial discordance in response in these parameters. The initial reduction in SBP and albuminuria independently correlated with cardiovascular protection: HR per 5 mmHg SBP reduction 0.97 (95% CI 0.94–0.99) and HR per decrement log albuminuria 0.87 (95% CI 0.76–0.99). Across all SBP categories at Month 6, a progressively lower cardiovascular risk was observed with a lower albuminuria level. This was particularly evident in patients who reached the guideline recommended SBP target of ≤130 mmHg.

Conclusion

The SBP and albuminuria response to ARB therapy is variable and discordant. Therapies intervening in the renin–angiotensin–aldosterone system with the aim of improving cardiovascular outcomes may therefore require a dual approach targeting both blood pressure and albuminuria.

Introduction

Albuminuria and blood pressure are both cardiovascular risk markers in patients with diabetes and nephropathy.1 Agents intervening in the renin–angiotensin–aldosterone system (RAAS) lower blood pressure and albuminuria and have been shown to be cardioprotective.2,3 As RAAS inhibitors are introduced as antihypertensive agents, current guidelines recommend to titrate these drugs towards the maximum blood pressure lowering dose. It is assumed that such a blood pressure-driven treatment strategy is paralleled by a reduction in albuminuria. However, two studies illustrate that both blood pressure and albuminuria responses are variable between individuals, and in addition that within an individual a blood pressure response is not always accompanied by a response in albuminuria and vice versa.4,5 Both the lowering of blood pressure as well as the lowering of albuminuria have been independently associated with improved cardiovascular protection.6,7 Based on this disparity in blood pressure and albuminuria response between and within an individual, one may argue that an approach focused solely on blood pressure reduction may not be the optimal strategy to confer cardiovascular protection.

To answer the question whether a treatment strategy that is concurrently aimed at reducing blood pressure and albuminuria would enhance the cardioprotective profile of RAAS-intervention, we performed a post hoc analysis of the combined data of the Reduction of Endpoints in NIDDM with the AII Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy Trial (IDNT) trials, dealing with patients with type 2 diabetes and reduced kidney function. We first assessed the short-term response in blood pressure and albuminuria between and within individuals. We subsequently investigated whether reductions in blood pressure and albuminuria are independently associated with cardiovascular protection. Finally, we tested whether the achieved levels of blood pressure and albuminuria are independently associated with improved cardiovascular outcomes.

Methods

DIAMETRIC database

We conducted a retrospective analysis of the DIAMETRIC database. The database was established in 2009 and comprised 3228 adult patients with type 2 diabetes and nephropathy participating in the RENAAL and IDNT trials. The detailed design, rationale, and study outcome for these trials have been previously published.8–11 Both trials investigated the efficacy of an angiotensin receptor blocker (ARB) (irbesartan in IDNT, losartan in RENAAL) on renal outcomes in subjects with type 2 diabetes and nephropathy. In addition, the IDNT trial included a calcium antagonist (amlodipine) treatment arm. For the purpose of analysis, we combined the calcium antagonist group with the placebo group of both trials. Inclusion criteria were similar but there were minor differences in detail for these trials. Patients with type 2 diabetes, hypertension, and nephropathy aged between 30 and 70 years were eligible for these trials. Serum creatinine levels ranged between 1.0 and 3.0 mg/dL. All subjects had proteinuria, defined as 24 h urinary protein excretion of >900 mg in the IDNT trial whereas for RENAAL patients a urinary albumin-to-creatinine ratio (UACR) of >300 mg/g or a 24 h urinary protein excretion >500mg/day was required. A 24 h UACR was calculated from the urinary albuminuria and creatinine data collected in IDNT. Exclusion criteria for both trials were type 1 diabetes or non-diabetic renal disease.

Patients randomized to study treatment were stepwise uptitrated in two periods of 4 weeks to achieve blood pressure target of at least 135/85 mmHg [50–100 mg losartan (RENAAL), 75–150 mg irbesartan (IDNT), or 2.5–10 mg amlodipine (IDNT)]. After the end of the titration period, the dosage of other antihypertensive drugs was increased or additional antihypertensive agents [but not angiotensin-converting enzyme inhibitors (ACE-Is) or ARBs in RENAAL and ACE-Is, ARBs, or calcium antagonists in IDNT] were added to achieve the target blood pressure.

The primary endpoint in each trial was essentially identical, consisting of the time to first event of doubling baseline serum creatinine, end stage renal disease, or death. Cardiovascular outcomes were also collected in both trials. The cardiovascular outcome for this study was the composite of myocardial infarction, stroke, hospitalization for heart failure, or cardiovascular death. All cardiovascular outcomes were adjudicated by an independent blinded endpoint committee using rigorous outcome definitions. All cardiovascular events were included in the analysis instead of limiting the analysis to events that occurred after 6 months. To establish the validity of this approach, a sensitivity analysis was conducted excluding the events that occurred during the first 6 months.

Blood pressure and albuminuria measurements

This post hoc analysis focuses on the blood pressure and albuminuria (defined as the albumin to creatinine ratio) response from baseline to Month 6. Blood pressure and albuminuria were measured in both the RENAAL and IDNT trials at baseline, Month 3, and Month 6. Patients included in this analysis were required to have their blood pressure measurement and collection of urine for albuminuria assessment not more than 1 day apart in order to obtain matched blood pressure and albuminuria values at baseline and Month 6. Systolic blood pressure response was defined as the difference between the Month 6 and baseline value. Albuminuria response at Month 6 for each patient was calculated as (1—ratio of Month 6 to baseline albuminuria) multiplied by 100%. On the basis of previous analyses, the Month 6 value was chosen because most parameters were measured at Month 6, the treatment effects were considered fully present, and few events occurred during the first 6 months. All patients originally randomized to treatment were considered in this analysis. If participants had missing blood pressure and/or albuminuria values at Month 6, the missing value was replaced by the last post-randomization value.

Statistical analyses

The changes in systolic blood pressure (SBP) and albuminuria were stratified in four categories: ≤15; −15–0; 0–15; ≥15 mmHg change in SBP and ≤30; −30–0; 0–30; ≥30% change in albuminuria. A multivariate cox model was used to assess the relationship between the magnitude of SBP and albuminuria change and risk for cardiovascular outcomes. For exploration of the hazard ratio (HR) profile, HRs (95% CI) for participants according to quartiles in SBP and log transformed albuminuria change was calculated. The variance of each quartile of SBP and albuminuria change was calculated by using the absolute floating risk method.12 The regression line for the risk estimates according to quintiles of Month 6 change in SBP and albuminuria was fitted using inverse variance weighting. Risk reductions per decrement log albuminuria are in the text described as percentage reduction [(1–hazard ratio)×100%]. The multivariate cox model included the following baseline covariates: age, gender, race, cardiovascular disease history, albuminuria, blood pressure-lowering medication (α-blocker, β-blocker, calcium antagonist, diuretics), seated SBP and diastolic blood pressure, estimated glomerular filtration rate, HbA1c, cholesterol, weight, smoking as well as the Month 6 change in albuminuria, seated SBP, diastolic blood pressure, eGFR, HbA1c, and weight. The multivariate cox model was stratified by treatment assignment and trial (RENAAL or IDNT). A backward selection model was used with the significance set at P < 0.05 to remove a covariate from the model. A multivariate cox model was also used to assess the relationship between the residual Month 6 SBP and albuminuria. The residual SBP was divided into four categories of approximate equal sample sizes and easy understandable thresholds: ≤130; 130–145; 145–160; >160 mmHg. The residual albuminuria was divided into four categories as well: ≤0.75; 0.75–1.5; 1.5–3.0; >3.0 g/g. For exploration of the hazard risk profile of the residual SBP and albuminuria, a cox model was used with SBP ≤130 mmHg or albuminuria ≤0.75 g/g as a reference group. For testing of combined effects of residual Month 6 SBP and albuminuria, an interaction term was added to the model. The multivariate analyses were conducted in the overall population and stratified for treatment and trial to remove potential confounding as a result of treatment assignment or trial characteristics. In an additional analysis, the multivariate analysis was also conducted in the ARB treatment arm separately to examine whether changes in albuminuria that resulted from ARB treatment have the same relationship with long-term cardiovascular outcomes. Continuous variables are reported as means and standard deviations. Categorical variables are reported as numbers and percentages. All analyses were conducted with SAS version 9.0 (SAS Institute, Cary, NC, USA).

Results

Baseline characteristics and blood pressure and albuminuria response

A total of 2900 patients had baseline and Month 6 SBP and albuminuria values available for the analysis (1428 RENAAL; 1472 IDNT). The baseline characteristics of these participants are shown in Table 1. Patients participating in these trials had similar baseline characteristics.

Table 1

Baseline characteristics of the 2900 subjects included in the present analysis

BP, blood pressure; UACR, urinary albumin to creatinine ratio.

The overall population is shown and the RENAAL and IDNT trials separately. Values are expressed as mean with standard deviation. UACR is expressed as median with inter-quartile range.

Table 1

Baseline characteristics of the 2900 subjects included in the present analysis

BP, blood pressure; UACR, urinary albumin to creatinine ratio.

The overall population is shown and the RENAAL and IDNT trials separately. Values are expressed as mean with standard deviation. UACR is expressed as median with inter-quartile range.

A discordant response in blood pressure and albuminuria was found in a considerable proportion of patients. Of the ARB assigned participants, 211 subjects (17.3%) showed a reduction in SBP but no reduction in albuminuria and 210 (17.2%) had no reduction in SBP but a reduction in albuminuria (Table 2). In the conventional treatment group, 507 (30.1%) and 236 (14.0%) had a discordant response in blood pressure and albuminuria.

Table 2

Patient distribution (number of patients as well as % of total in parenthesis) according to change in albuminuria and systolic blood pressure during the first 6 months of therapy for the ARB and conventional treatment group

The sum of the numbers and percentage in the boxes indicate the proportion of all subjects with a concordant respectively discordant blood pressure and albuminuria response.

Table 2

Patient distribution (number of patients as well as % of total in parenthesis) according to change in albuminuria and systolic blood pressure during the first 6 months of therapy for the ARB and conventional treatment group

The sum of the numbers and percentage in the boxes indicate the proportion of all subjects with a concordant respectively discordant blood pressure and albuminuria response.

Systolic blood pressure and albuminuria reduction and cardiovascular outcome

A larger reduction in blood pressure during the first 6 months was independently associated with a lower risk for cardiovascular events (composite of myocardial infarction, stroke, hospitalization for heart failure, or cardiovascular death) in the long term (Figure 1). Each 5 mmHg reduction in blood pressure during the first 6 months was independently associated with a risk reduction of 3% (95%CI 1–6%; P = 0.021) in cardiovascular events (Figure 1). Additionally, a larger reduction in albuminuria during the first 6 months was independently associated with a lower risk for cardiovascular events in the long term (Figure 1). Each log unit decrement in albuminuria was associated with a 13% (95%CI 1–24%; P = 0.032) risk reduction for cardiovascular events. Similarly, in patients treated with an ARB, each decrement in log albuminuria was associated with 20% (95%CI 4–34%; P = 0.019) risk reduction for cardiovascular events. To establish the robustness of this finding, we conducted a sensitivity analysis. Although all cardiovascular events were included in our analysis, we repeated the analysis limiting the cardiovascular events to only those arising after the 6 months time-point and noted a similar pattern.

Figure 1

Relationship between Month 6 change in blood pressure and albuminuria and cardiovascular outcome. Boxes represent the point-estimate and the bars their 95% confidence interval. The variance of each quintile of change in albuminuria was calculated by using the absolute floating risk method. The regression line for the risk estimates according to quartiles in change in albuminuria was fitted using inverse variance weighting. The hazard ratio (95% confidence interval) reported in the figure is based on continuous data. The cardiovascular outcome was the composite of myocardial infarction, stroke, hospitalization for heart failure, or cardiovascular death.

Residual systolic blood pressure and albuminuria and cardiovascular outcome

The relationship between residual Month 6 SBP and albuminuria is shown in Figure 2. A progressively lower cardiovascular risk was observed as the residual albuminuria decreased from 4.0 to 0.5 g/g and the residual SBP decreased from 170 to 120 mmHg. It should be noted however that the point estimate for cardiovascular risk in patients with an average Month 6 SBP of 120 mmHg was slightly higher compared with those with a SBP of 140 mmHg.

Figure 2

Relationship between residual Month 6 blood pressure or albuminuria and cardiovascular outcome. Boxes represent the point-estimate and the bars their 95% confidence interval. The variance of each quartile of residual blood pressure or albuminuria was calculated by using the absolute floating risk method. The regression line for the risk estimates according to quartiles in change in albuminuria was fitted using inverse variance weighting. The cardiovascular outcome was the composite of myocardial infarction, stroke, hospitalization for heart failure, or cardiovascular death.

The cardiovascular risk according to combined residual SBP and albuminuria demonstrated that across all SBP categories, a progressively lower cardiovascular risk was observed with a lower albuminuria level (Figure 3). The presence of a low SBP level in those who did not achieve a low albuminuria level did not confer additive protection against cardiovascular events. This was particularly evident in the strata of patients who achieved the SBP goal below 130 mmHg. There was no interaction of the achieved Month 6 albuminuria over SBP (P = 0.664).

Figure 3

Risk for cardiovascular events by achieved Month 6 albuminuria and systolic blood pressure. The table below the graph shows the number of patients in each category with the corresponding cardiovascular event rate per 100 patients years in brackets.

Discussion

The data of this study indicate that a low residual SBP in combination with a low residual albuminuria leads to optimal cardiovascular risk protection. However, using a blood pressure-based titration regime, many patients do not achieve reductions in albuminuria despite a reduction in SBP. This dissociation was observed in individuals treated with ARB treatment and conventional antihypertensive treatment. These data suggest that one should monitor not only the blood pressure, but also the albuminuria response and adjust medication if necessary in order to optimally benefit in terms of cardiovascular outcome.

Supposedly, the albuminuria response depends at least to a certain extent on the blood pressure response. However, the results of this study indicate that in a significant proportion of patients an albuminuria response is discordant with the response in SBP. The exact reasons for this discordance in response are difficult to establish from the current study, but several possibilities exist. First, it could be possible that the clinical blood pressure measurements do not accurately reflect true blood pressure and that the blood pressure response assessed by 24 h ambulatory blood pressure, central blood pressure, or glomerular blood pressure monitoring is better coupled to the albuminuria response.13–15 Second, it could be possible that differences in baseline parameters, diabetes control, or concomitant blood pressure lowering drugs differed across subgroups. The use of concomitant drugs and diabetes control was similar across the defined groups of blood pressure and albuminuria change which makes a possible interference with the discordant effect and the cardiovascular risk data unlikely. Interestingly, in a logistic multivariate analysis we found that body weight was the only baseline parameter associated with a discordant response. This might be expected as recent data show that higher body weight was associated with a greater albuminuria response while any change in blood pressure response upon RAAS inhibition has, to our knowledge, never been demonstrated.16,17 Third, differences in tissue-specific RAAS-activity and differences in tissue penetration are another hypothetical option that may explain the disparity in blood pressure and albuminuria response within an individual. In this respect, the albuminuria response depends on the extent of intra-renal RAAS-blockade while the SBP response depends on systemic vasculature RAAS-inhibition. Pre-clinical studies have indeed shown that inhibition of extra-renal RAAS plays an important role in mediating blood pressure control.18 However, further studies establishing the relative roles of the intra-renal RAAS as opposed to the extra-renal RAAS are clearly warranted to dissect the underlying mechanisms of the disparity in albuminuria and blood pressure response within an individual.

It is beyond doubt that blood pressure should be tightly controlled to lower the risk of cardiovascular disease.19 However, in addition to blood pressure, albuminuria is an independent cardiovascular risk predictor.6 The results of our analysis confirm previous post hoc analyses indicating that regimens that lower albuminuria independent of optimal blood pressure control are associated with a reduction in cardiovascular protection. The LIFE trial showed that reductions in albuminuria conferred by a losartan-based treatment explained one-fifth of the risk reduction on cardiovascular complications when compared with atenolol-based treatment.7 In addition, a small study in patients with type 2 diabetes without hypertension and microalbuminuria demonstrated that sustained reductions in albuminuria distinguished individuals in their risk of cardiovascular events. The fact that blood pressure levels did not change or even rose during the course of this study, provides further support that reductions in albuminuria per sé were the driving parameter for cardiovascular protection.20 Unfortunately, however, there is no prospective randomized controlled data in patients with type 2 diabetes that determine whether albuminuria lowering in itself is associated with cardiovascular protection.

The clinical implication of our study is that a treatment approach concurrently aimed at optimal blood pressure and optimal albuminuria reduction within an individual will result in optimal cardiovascular protection. RAAS-inhibitors are nowadays titrated towards the optimal blood pressure goal desired and tolerated.21 The data of this study indicate that such an approach is not sufficient to achieve optimal cardiovascular protection as many patients who achieve optimal blood pressure goal do not have a sufficient albuminuria response and consequently remain at high cardiovascular risk. The results of this study suggest that a dual efficacy approach both pursuing optimal blood pressure as well as albuminuria reduction may further attenuate the risk of cardiovascular disease. Recent studies have shown that indeed increasing the dose of ARBs beyond the recommended dosing schedules may result in a levelling of the blood pressure response but a still increasing response in decreasing albuminuria.22–24 Some caution is warranted. The ONTARGET trial results indicate that targeting blood pressure towards normalcy does not always guarantee that optimal cardiovascular protection is achieved.25 However, one needs to realize that ACE-I and ARBs may cause hypotension and/or increase serum potassium. Both effects may increase cardiovascular risk. Indeed, our data shows increased cardiovascular risk when SBP levels fall below 120 mmHg. These data are in line with other post hoc analyses of clinical trial data.26–28 Whether the increased risk is the consequence of a too low SBP or the consequence of other baseline co-morbidities warrants further research. Nevertheless, these effects may blunt the beneficial cardiovascular effects of albuminuria and blood pressure lowering. We therefore recommend that titration should be based on individual response rather than fixed titration schedules and that one not only focuses on the beneficial efficacy effects, but also optimize the response of drugs on parameters that negatively influence outcome.29

Some limitations of our analysis should be mentioned. This is a post hoc analysis of trial data and the conclusions can only be considered as hypothesis generating. In addition, both the RENAAL and IDNT trials were not primarily designed to establish the effects of ARB or calcium antagonist therapy on cardiovascular endpoints (in particular the selection process focused on renal patients). Strengths of the analysis include the large number of patients available and the rigorous methods of data collection, recording and analysis, allowing precise estimation of the effect sizes.

In conclusion, the SBP and albuminuria response to ARB therapy does not always run in parallel. The cardiovascular risk is dependent on adequate blood pressure control, but also showed a clear dependence on the achieved albuminuria regardless of the level of SBP. These results suggest that therapies intervening in the RAAS with the aim to improve cardiovascular outcomes should not only titrate the drug to the lowest blood pressure goal wanted but may require a dual approach of lowering both blood pressure and albuminuria.

Funding

This work was supported by Merck & Co for the RENAAL trial. Sanofi-Synthelabo and Bristol Myer Squibb sponsored the IDNT trial.

Conflict of interest: The RENAAL trial was sponsored by Merck & Company. DdZ HHP and GR received financial support from Merck & Co for their participation in the steering committee of the RENAAL trial. The IDNT trial was sponsored by Bristol Myer Squibb Institute for Medical Research and Sanofi-Synthelabo. T.B. received research grants from Bristol Myer Squibb. F.A.H., P.A.G., G.D.L., J.B., D.P. and H.J.L.H. have no conflicts of interests to declare.

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: journals.permissions@oup.com

Topic:

• systolic blood pressure
• diabetes mellitus, type 2
• blood pressure
• cardiovascular system
• albuminuria

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