Diabetes Care
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online September 5, 2007
Diabetes Care 30:3119-3121, 2007
DOI: 10.2337/dc07-0960
© 2007 by the American Diabetes Association
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dc07-0960v1
30/12/3119    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zandbergen, A. A.M.
Right arrow Articles by Bootsma, A. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zandbergen, A. A.M.
Right arrow Articles by Bootsma, A. H.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Cardiovascular and Metabolic Risk
Original Research

Change in Albuminuria Is Predictive of Cardiovascular Outcome in Normotensive Patients With Type 2 Diabetes and Microalbuminuria

Adrienne A.M. Zandbergen, MD, PHD1, Liffert Vogt, MD2, Dick de Zeeuw, MD, PHD2, Steven W.J. Lamberts, MD, PHD1, Rob J.T.H. Ouwendijk, MD, PHD3, Marinus G.A. Baggen, MD, PHD3 and Aart H. Bootsma, MD, PHD1

1 Department of Internal Medicine, Erasmus University Medical Centre, Erasmus University Rotterdam, Rotterdam, the Netherlands
2 Department of Internal Medicine and Clinical Pharmacology, University Medical Centre Groningen, Groningen, the Netherlands
3 Department of Internal Medicine, Ikazia Hospital Rotterdam, Rotterdam, the Netherlands

Address correspondence and reprint requests to Adrienne A.M. Zandbergen, MD, PHD, Erasmus University Medical Centre, Internal Medicine, 's Gravendijkwal 230, 3015 CE, Rotterdam, Netherlands. E-mail: adrienne_zandbergen{at}yahoo.com

Abbreviations: RAS, renin-angiotensin system


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
Microalbuminuria is associated with cardiovascular complications and all-cause mortality in patients with diabetes (1–3). Inhibitors of the renin-angiotensin system (RAS) protect renal and cardiac function in these patients, at least partly independent of the associated blood pressure reduction (4–9). Recently, a few studies showed that reduction in albuminuria in hypertensive diabetic patients reduces the risk of subsequent cardiovascular events (10–12). The question remains whether this risk reduction is explained by the reduction of high blood pressure. No data are available for normotensive diabetic patients. Therefore, we investigated whether sustained change in albuminuria independently predicts cardiovascular outcome in patients with type 2 diabetes and microalbuminuria but without hypertension.


   RESEARCH DESIGN AND METHODS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
The present study is a prospective follow-up study of 67 normotensive patients (baseline blood pressure ≤140/90 mmHg without antihypertensive treatment) with type 2 diabetes and microalbuminuria (urinary albumin excretion 20–200 mg/l), who participated in a previously published, larger, randomized, double-blind, placebo-controlled, multicenter trial investigating the short-term effects of the angiotensin-receptor antagonist losartan on microalbuminuria (7). Exclusion criteria included a history of macrovascular complications and a baseline serum creatinine level >150 µmol/l.

After the original 20-week study period, a cohort of 67 patients from that study was prospectively followed during mean ± SEM 4.7 ± 0.1 years. They were recruited on the basis of their address and received standard medical care. Data were collected on current and past health, medication use, blood pressure, renal function, and albuminuria, which was annually assessed in morning spot urines. The end point was a composite of death, cardiovascular disease, cerebrovascular events, and peripheral artery disease.

Paired Student's t test was used for comparisons within similar variables. Regarding the rate of change in albuminuria from baseline over each year, three groups were discerned: one with reduction of albuminuria of ≥30%, one with stable albuminuria (change <30%), and one with rapid progression of albuminuria of at least 30%. The correlation between rate of change in albuminuria at 1 year and cumulative event-free survival was analyzed with the Kaplan-Meier method, the log-rank test, and multivariate Cox regression. The 95% CI of the hazard ratio (HR) was calculated as the exponent of the regression coefficient. P values <0.05 defined statistical significance. We used SPSS for Windows (version 12.0; SPSS, Chicago, IL) for all analyses.


   RESULTS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
Baseline characteristics of the three groups, including blood pressure and albuminuria, did not differ significantly, with the exception of age, for which we corrected. Albuminuria reduced from 69.1 mg/l at baseline to 39.4 mg/l after 1 year (mean difference –29.7 mg/l [95% CI –39.7 to –19.8], P < 0.0001) and returned to 62.0 mg/l at the end of follow-up in the group with albuminuria reduction. In patients with rapid progression of albuminuria, mean levels were 84.3 mg/l at baseline, 223.3 mg/l after 1 year (139.0 mg/l [46.3–209.7], P < 0.01), and 354.1 mg/l at the end of follow-up. Albuminuria levels did not change significantly in the group with stable albuminuria. Importantly, the course of blood pressure was similar in the three groups, without significant changes in systolic or diastolic blood pressure (Fig. 1).


Figure 1
View larger version (12K):
[in this window]
[in a new window]

  		Figure 1— Course of urinary albumin excretion and blood pressure during follow-up in the three groups of urinary albumin excretion change at 1 year (•, urinary albumin excretion difference <30% [not significant]; {blacksquare}, urinary albumin excretion reduction >30% [P < 0.001]; {diamond}, urinary albumin excretion progression >30% [P < 0.01]). The course of blood pressure was similar in the three groups; changes during follow-up: not significant.

 
During follow-up, 14 patients (21%) reached the composite end point. A significant difference in event-free survival was observed between the three groups (P = 0.02). Patients with rapid progression of albuminuria were at highest risk to reach the end point, whereas patients with reduction in albuminuria of ≥30% were at lowest risk. After adjustment for sex, age, systolic blood pressure, total–to–HDL cholesterol ratio, and current smoking in a multivariate Cox regression model, change of albuminuria remained an independent, significant predictor (HR 5.1 [95% CI 1.5–18.1], P = 0.01).

Relevant medication during follow-up was used similarly in the three groups. Following the original study protocol, 63 patients (95%) received an RAS inhibitor because of microalbuminuria. At the end of follow-up, 62 patients (93%) still used RAS inhibition. Moreover, neither statin nor aspirin use differed between groups.


   CONCLUSIONS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
This study demonstrates that normotensive patients with type 2 diabetes and miroalbuminuria run a marked risk for cardiovascular complications. The risk depends on the rate of 1-year change in urinary albumin excretion. Patients with rapid progression of albuminuria were at highest risk, whereas patients with regression of albuminuria had the lowest risk. This association persisted after adjustment for classic cardiovascular risk factors.

Besides reducing blood pressure, RAS inhibitors are effective in preserving renal and cardiac function in diabetic patients (4–9). Moreover, they reduce albuminuria up to 40%, significantly more than other classes of antihypertensive drugs (4). Since albuminuria is strongly associated with cardiovascular outcome, changes in albuminuria during treatment might reflect changes in cardiovascular disease risk (13,14). A few studies recently showed that reduction of albuminuria in hypertensive diabetic patients reduces the risk of subsequent cardiovascular events (10–12,15). However, these studies investigated hypertensive patients, thereby leaving open the possibility that blood pressure lowering explains the cardiovascular risk reduction, with albuminuria change just an innocent bystander. To our knowledge, our study is the first demonstrating that, even with no appreciable changes or even rises in blood pressure, change in albuminuria differentiates the cardiovascular outcome in type 2 diabetic patients without hypertension.

An important limitation of this study is the small sample size. Nonetheless, the association that we observed between changes in albuminuria and cardiovascular outcome was statistically significant in multivariate analysis. The strength of our study lies in the fact that we studied type 2 diabetic patients with microalbuminuria but without hypertension at baseline in a prospective design. Clearly, this study needs further follow-up in larger cohorts.

In summary, sustained reduction in albuminuria reflected cardiovascular risk reduction in type 2 diabetic patients without hypertension. Hence, albuminuria change during treatment seems to reveal therapeutic responsiveness independent of blood pressure changes and is therefore useful as a modifiable treatment goal. These observations advocate a more aggressive approach to treating albuminuria in addition to more aggressive cardioprotective treatment in normotensive diabetic patients with elevated levels of albuminuria.


   Acknowledgments
 
The authors thank the following investigators: Drs. T.L.J.M. van der Loos and F.J.M. Klessens-Godfroy (Rotterdam Eye Hospital, Rotterdam, the Netherlands), Dr. J.W.F. Elte (Sint Franciscus Hospital, Rotterdam, the Netherlands), Dr. R.J.M. van Leendert (Albert Schweitzer Hospital, Zwyndrecht, the Netherlands), Dr. S.G.T Hulst (Vlietland Hospital, Schiedam, the Netherlands), and Dr. J.W. van der Beek-Boter (Hofpoort Hospital, Woerden, the Netherlands).

These data were presented in abstract form as a poster at the scientific meeting of the International Diabetes Federation at the Cape Town International Convention Centre, Cape Town, South Africa, on 4 December 2006.


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 5 September 2007. DOI: 10.2337/dc07-0960.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication May 19, 2007. Accepted for publication August 26, 2007.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

  1. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yususf S; HOPE Study Investigators: Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 286:421–426, 2001[Abstract/Free Full Text]
  2. Arnlov J, Evans JC, Meigs JB, Wang TJ, Fox CS, Levy D, Benjamin EJ, D'Agustino RB, Vasan RS: Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation 112:969–975, 2005[Abstract/Free Full Text]
  3. Yuyun MF, Adler AI, Wareham NJ: What is the evidence that microalbuminuria is a predictor of cardiovascular disease events? Curr Opin Nephron Hypertens 14:271–276, 2005
  4. Ruilope LM, Segura J: Losartan and other angiotensin II antagonists for nephropathy in type 2 diabetes mellitus: a review of the clinical trial evidence. Clin Ther 25:3044–3064, 2003[Medline]
  5. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869, 2001[Abstract/Free Full Text]
  6. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878, 2001[Abstract/Free Full Text]
  7. Zandbergen AA, Baggen MG, Lamberts SW, Bootsma AH, de Zeeuw D, Ouwendijk RJ: Effect of losartan on microalbuminuria in normotensive patients with type 2 diabetes mellitus: a randomized clinical trial. Ann Intern Med 139:90–96, 2003[Abstract/Free Full Text]
  8. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; LIFE Study Group: Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertensive study (LIFE): a randomised trial against atenolol. Lancet 359:995–1003, 2002[Medline]
  9. Heart Outcomes Prevention Evaluation Study Investigators: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342:145–153, 2000[Abstract/Free Full Text]
  10. Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, Dahlof B, Devereux RB, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wan Y: Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. Hypertension 45:198–202, 2005[Abstract/Free Full Text]
  11. De Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM: Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110:921–927, 2004[Abstract/Free Full Text]
  12. Yuyun MF, Dinneen SF, Edwards OM, Wood E, Wareham NJ: Absolute level and rate of change of albuminuria over 1 year independently predict mortality and cardiovascular events in patients with diabetic nephropathy. Diabet Med 20:277–282, 2003[Medline]
  13. De Zeeuw D: Albuminuria, not only a cardiovascular/renal risk marker, but also a target for treatment? Kidney Int 68:1899–1901, 2005[Medline]
  14. Burnier M, Zanchi A: Blockade of the renin-angiotensin-aldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes. J Hypertens 24:11–25, 2006[Medline]
  15. Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, Dahlof B, Snapinn SM, Wan Y, Lyle PA: Does albuminuria predict cardiovascular outcomes on treatment with losartan versus atenolol in patients with diabetes, hypertension, and left ventricular hypertrophy? The LIFE study. Diabetes Care 29:595–600, 2006[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?



This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dc07-0960v1
30/12/3119    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zandbergen, A. A.M.
Right arrow Articles by Bootsma, A. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zandbergen, A. A.M.
Right arrow Articles by Bootsma, A. H.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum