measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2...

J Am Soc Nephrol. 2012 Sep 28; 23(10): 1717–1724.Published online 2012 Aug 30. doi: 10.1681/ASN.2012030252

PMCID: PMC3458466

Measurable Urinary Albumin Predicts Cardiovascular Risk amongNormoalbuminuric Patients with Type 2 DiabetesPiero Ruggenenti, Esteban Porrini, Nicola Motterlini, Annalisa Perna, Aneliya Parvanova Ilieva, Ilian Petrov Iliev,Alessandro Roberto Dodesini, Roberto Trevisan, Antonio Bossi, Giuseppe Sampietro, Enrica Capitoni, FlavioGaspari, Nadia Rubis, Bogdan Ene-Iordache, Giuseppe Remuzzi, and for the BENEDICT Study InvestigatorsClinical Research Center for Rare Diseases, “Aldo & Cele Daccò,” Mario Negri Institute for Pharmacological Research, Bergamo, Italy;Units of Nephrology andDiabetology andResearch Foundation, Azienda Ospedaliera, “Ospedali Riuniti di Bergamo,” Bergamo, Italy;Unit of Diabetology, Treviglio Hospital, Treviglio, Italy; andEpidemiological Observatory, “Azienda Sanitaria Locale della Provincia di Bergamo,” Bergamo, ItalyCorresponding author.

P.R. and E.P. contributed equally to this work.Correspondence: Dr. Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori Science andTechnology Park, Kilometro Rosso Via Stezzano, 87. 24126 Bergamo, Italy., Email: [email protected], Email:[email protected] 2012 Mar 9; Accepted 2012 Jul 11.Copyright © 2012 by the American Society of Nephrology

AbstractMicro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients withtype 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk isunknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic DiabetesComplication Trial (BENEDICT), all of whom received angiotensin-converting enzyme inhibitor (ACEI)therapy at the end of the trial and were followed for a median of 9.2 years. The main outcome was time tothe first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral arteryrevascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced amain outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independentlypredicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02–1.08). Second-degreepolynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria andevents without thresholds. Considering the entire study population, even albuminuria at 1–2 μg/min wassignificantly associated with increased risk compared with albuminuria <1 μg/min (HR, 1.04; 95% CI,1.02–1.07). This relationship was similar in the subgroup originally randomly assigned to non-ACEItherapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low andwas not significantly associated with albuminuria. Taken together, among normoalbuminuric patients withtype 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. Theassociation with risk is continuous but is lost with early ACEI therapy.

Patients with type 2 diabetes mellitus and micro- or macroalbuminuria (i.e., a urinary albumin excretion[UAE] rate of 20–200 μg/min or >200 μg/min, respectively) have a risk for cardiovascular death that is

*† * * * * *‡ ‡ § ǁ ¶

* * * *†*†‡¶§ǁ

Measurable Urinary Albumin Predicts Cardiovascular Risk among Norm... http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458466/?report=printable

1 de 15 7/08/2015 2:52 a. m.

Primary Composite End-Point

2–12 times that observed in patients with less albuminuria. This largely accounts for the excesscardiovascular mortality observed in patients with diabetes compared with age-matched persons withoutthe disease. Conversely, diabetic patients with UAE <20 μg/min (the upper limit of what is generallyconsidered the normal range) are supposed to have a cardiovascular risk close to that of the generalpopulation. However, this cutoff was introduced a priori in clinical use and research based on theobservation that 95% of “normal” individuals had excretion rates below that limit. Whether this valuereflects a real threshold for cardiovascular risk or whether any measurable amount of albuminuria bears asignificant risk, even within the normal range, is unknown, particularly in the diabetic population. Whetherthere is a level for albuminuria that differentiates patients who need cardioprotective intervention fromthose with a low risk who are unlikely to be affected by any treatment is also elusive. This is a major healthissue because persons with normoalbuminuria account for the large majority of the diabetic population, andpromptly identifying those at risk and providing them with preventive strategies before they progress tomore severe and possibly irreversible stages of the disease might have major clinical implications.To address the above issues, we evaluated a large cohort of patients with type 2 diabetes and baseline UAE<20 μg/min who were included in the BErgamo NEphrologic Diabetes Complication Trial(BENEDICT-A) and eventually followed for approximately 10 years. In BENEDICT, at similar BPcontrol, angiotensin-converting enzyme inhibitor (ACEI) treatment with trandolapril alone or incombination with the nondihydropyridine calcium-channel blocker verapamil halved the incidence ofmicroalbuminuria compared with verapamil alone or placebo.We primarily sought to address whether and to what extent baseline albuminuria was associated withlong-term incidence of fatal and nonfatal cardiovascular events in the above population. Secondarily, weexplored whether earlier treatment with an ACEI translated into more effective cardioprotection in the longterm and whether there was a threshold for baseline albuminuria above which this effect became apparent.ResultsBaseline CharacteristicsMedian UAE at inclusion was 5.24 (range, 0.44–19.85) μg/min. UAE exceeded 14 μg/min in only 10% ofparticipants (Table 1). Baseline characteristics of study participants were similar to those of the 139 patientswho did not enter the BENEDICT extension study, with the exception of a higher prevalence of men, lowerhemoglobin A (HbA ), and lower LDL-to-HDL cholesterol ratio in included participants (SupplementalTable 1). A similar proportion of patients originally randomly assigned in BENEDICT to trandolapril ornon-ACEI therapy was receiving ACEI (87.5%) or statin (50.5%) therapy during the extension study.OutcomesDuring a median follow-up of 9.12 (interquartile range, 6.16–9.86) years, 168 patients died, 37 (22%) ofcardiovascular causes. Overall, 212 major cardiovascular events were observed in 189 patients.

Overall, first onset of a component of the composite end point of majorcardiovascular events was observed in 189 of the 1208 randomly assigned participants (15.6%). In 24 cases(12.7%), the event was fatal. In addition to 3 sudden-death events (1.6%), there were 105 (55.6%), 39(20.6%), and 31 (16.4%) events related to coronary, cerebrovascular, or peripheral artery disease,respectively, and 11 hospitalizations (5.8%) due to worsening of congestive heart failure (Table 2).Throughout the whole observation period, there were 2.14 patients with the end point event every 100patients per year. Overall, there were 55 end point events (4 fatal) during BENEDICT-A and 133 (20 fatal)during the extension study.

1,2

1,3,4

5–78

9

9,10

1c 1c


2 de 15 7/08/2015 2:52 a. m.

Baseline Characteristics and Cardiovascular Risk

Sensitivity Analyses

Cardiovascular Risk According to ACEI Therapy

Compared with patients without cardiovascular events, those progressing to the end point were older andmore frequently male, more frequently reported a cardiovascular event before study inclusion, and hadmore albuminuria and higher HbA and serum LDL-to-HDL cholesterol ratio (Table 1). Other baselinecharacteristics (including BP; concomitant antihypertensive, antidiabetic, and lipid-lowering treatment; andwhether patient was allocated to ACEI therapy) were similar between groups with or without end pointevents.

At univariable Cox proportional hazards regressionanalysis, older age; male sex; a longer duration of diabetes; previous cardiovascular events; and higherLDL-to-HDL cholesterol ratio, creatinine levels, and albuminuria levels were significantly associated witha higher risk for new-onset cardiovascular events (Table 3). At multivariable analysis, albuminuria wassignificantly associated with risk for cardiovascular events (hazard ratio [HR], 1.06; 95% confidenceinterval [CI], 1.02–1.08). On average, for 1 μg/min excess of albuminuria at baseline there was a 6% riskfor progression to the end point on follow-up. Other independent predictors of events were older age, malesex, previous cardiovascular events, higher HbA levels, and higher LDL-to-HDL cholesterol ratio. Nosignificant interaction between albuminuria and the other baseline covariates was observed. Theassumption of proportionality was not violated (Schoenfeld residuals: P=0.26).The second-degree polynomial transformation of albuminuria described the relationship with thecardiovascular end point with lower deviance (best goodness of fit) than the first degree (logarithmic)transformation (931.32 versus 934.27, respectively). Modeling baseline albuminuria by second-degreepolynomial transformation in the multivariable analysis showed a continuous nonlinear relationshipbetween albuminuria and cardiovascular events (Figure 1). A significant excess risk for progression to theend point was already evident for a UAE ranging from 1 to 2 µg/min compared with an excretion <1µg/min (HR, 1.04; 95% CI, 1.02–1.07) taken as the reference value. The risk for events compared with thereference albuminuria level tended to plateau (HR, 2.49; 95% CI, 1.56–4.00) between albuminuria valuesof 13 and 14 µg/min (Figure 1 and Supplemental Table 2). Results were similar when baseline albuminuriawas modeled with a spline function (data not shown). Cardiovascular risk at higher levels of albuminuriawas not considered because of the too small number of patients and events.

Relationships between albuminuria and outcomes similar to those described in thewhole study group were observed when the analyses were restricted to low-risk patients without a historyof cardiovascular events at inclusion or with persistent normoalbuminuria throughout BENEDICT, as wellas when cardiovascular events were considered independent of revascularizations and amputations or whenonly coronary events were analyzed (data not shown). Unlike BP, albuminuria at the end ofBENEDICT—that is, at baseline of the extension study—predicted cardiovascular events on subsequentfollow-up at univariate or multivariable analyses (odd ratios, 1.41 [95% CI, 1.15–1.74], P=0.001, and 1.29[95% CI, 1.04–1.60], P=0.001, respectively). Consistently, patients with persistent low-range comparedwith those with persistent high-range normoalbuminuria (i.e., albuminuria <1 SD or >1 SD of the mean atbaseline or at BENEDICT last visit, respectively) had a three-fold lower incidence of cardiovascular eventsduring the extension study (8% versus 24%; P=0.027).

Baseline characteristics of patients who had been originallyallocated to ACEI therapy with trandolapril alone or combined with verapamil in BENEDICT were similarto those of patients randomly assigned to non-ACEI therapy with verapamil alone or placebo. Eighty-fourof the 603 patients (13.9%) originally randomly assigned to ACEI therapy had at least one majorcardiovascular event compared with 105 of the 605 patients (17.4%) randomly assigned to non-ACEItherapy (P=0.08). During BENEDICT, 27 (4.5%) participants receiving ACEI therapy progressed to theend point compared with 28 (4.6%) receiving non-ACEI therapy (P=0.49). During the extension study,however, 57 patients receiving ACEI therapy progressed to the end point compared with 77 receiving

1c

1c

11


3 de 15 7/08/2015 2:52 a. m.

non-ACEI therapy, and the incidence of events was significantly lower in those with ACEI (9.5% versus12.7%; P=0.043).As in the study group considered as a whole, a continuous significant incremental risk for cardiovascularevents for each 1 µg/min increase in albuminuria at baseline was observed in patients originally randomlyassigned to non-ACEI therapy considered separately. Again, in this group a significant increase was alreadyevident for a UAE ranging from 1 to 2 µg/min compared with <1 µg/min (HR, 1.02; 95% CI, 1.01–1.074)taken as the reference value. The risk for events tended to plateau (HR, 3.15; 95% CI, 1.76–5.63) betweenalbuminuria values of 13 and 14 µg/min (Figure 2 and Supplemental Table 2). Of note, however, in patientsoriginally randomly assigned to ACEI therapy, the risk for major cardiovascular events was uniformly lowat any considered level of albuminuria at baseline, and no significant association was observed between anyincrement in albuminuria and cardiovascular events during the whole study period (Figure 2 andSupplemental Table 2).DiscussionIn this longitudinal observational study of >1000 patients with type 2 diabetes and normoalbuminuria, wefound a continuous relationship between UAE rate at inclusion and incidence of major cardiovascularevents during approximately 10 years of follow-up. For each 1 μg/min excess in baseline albuminuria, therewas a progressive incremental risk for cardiovascular events up to a UAE of 13–14 μg/min. Above thislevel, the number of patients was too small to evaluate any relationship between albuminuria and events.The incremental risk for events, compared with the reference risk observed with a UAE <1 μg/min, wasalready evident at an excretion rate ranging from 1 to 2 μg/min. The incremental incidence ofcardiovascular events observed for each 1 μg/min excess in baseline UAE was significant in the studygroup as a whole as well as in the subgroup of patients who had been originally randomly assigned inBENEDICT to non-ACEI therapy with verapamil alone or placebo. Of note, however, the associationbetween albuminuria and events was not significant in patients who had been randomly assigned to ACEItherapy with trandolapril alone or in combination with verapamil. Actually, in this subgroup the risk forevents was uniformly low, independent of the extent of albuminuria at baseline.The above findings were not explained by differences in patient characteristics or concomitant treatmentsbecause demographic, clinical, and laboratory variables at baseline, as well as targets for antihypertensive,antidiabetic, and lipid-lowering therapy throughout the whole observation period, were similar betweentreatment groups. Thus, the finding that patients originally randomly assigned to trandolapril duringBENEDICT tended to have fewer cardiovascular events than those who received the same treatment onlyafter inclusion in the extension study was consistent with the hypothesis that early ACEI therapy is morecardioprotective than late intervention. These data—which require confirmation in ad hoc prospectivestudies—extend previous evidence of sustained long-term benefit of early intensified metabolic control inan extension study of the Diabetes Control and Complications Trial and suggest that the same “memory”effect could apply also to ACEI, as already observed in the Heart Outcomes Prevention Evaluation (HOPE)study extension.A qualifying aspect of the present study was that for the first time evidence for a continuous relationshipbetween albuminuria and risk was formally provided in patients with normoalbuminuria to start with. TheHOPE study found that in patients at increased cardiovascular risk, the relationship between albuminuriaand cardiovascular events extended to as low as 0.5 mg of urinary albumin for 1 mmol of urinarycreatinine, while the Losartan Intervention For End-point reduction in hypertension (LIFE) study found asimilar relationship between albuminuria and events among patients with left ventricular hypertrophy. TheFramingham Heart Study showed that 6-year risk for cardiovascular disease was three-fold higher innonhypertensive, nondiabetic persons with a urinary albumin-to-creatinine ratio above the sex-specific

12

13

14

15


4 de 15 7/08/2015 2:52 a. m.

median (3.9 mg/min for men and 7.5 mg/min for women) than in those with a ratio below that level.Consistently, the Prevention of Renal and Vascular End Stage Disease (PREVEND) study found thatindependent of the effects of other cardiovascular risk factors, UAE was a predictor of cardiovascularmortality in the general population; the excess cardiovascular risk was already apparent at levels currentlyconsidered to be normal. All the preceding studies, however, included patients with a UAE ranging fromvery low levels, in the so-called normoalbuminuric range, to the micro- and even macroalbuminuric ranges.Thus, those results were largely driven by the well known association between micro- or macroalbuminuriaand excess cardiovascular risk. Conversely, the present study allows us to conclude that, as for BP, theconcept of a threshold level to define normality is inconsistent with available data and that any degree ofmeasurable albuminuria—that is, a urinary albumin concentration close to the detection limit (1–2 μg/ml)of the methods commonly used to measure urinary albumin (such as nephelometry or immunoturbidimetry)—bears a significant risk for cardiovascular events.The preceding findings may have practical implications because albuminuria can be reduced byamelioration of insulin sensitivity, weight loss, BP, and blood glucose reduction and renin-angiotensin system inhibitor therapy. In the long run, these interventions are expected to prevent ordelay end-organ damage. However, whether the above interventions are uniformly beneficial throughoutthe whole range of normoalbuminuria (or, rather, whether there is a threshold below which specificintervention is not associated with appreciable benefits) is unknown.In this regard, it is noteworthy that in this study, the relationship between albuminuria and cardiovascularevents was not appreciable in patients allocated to ACEI therapy during BENEDICT. Actually, in thistreatment group baseline albuminuria was no longer predictive of cardiovascular events throughout thewhole observation period. This was probably explained by a trend toward a progressively largercardioprotective effect of trandolapril for progressively increasing levels of albuminuria. Independent of theabove, during the extension study we observed fewer events in patients who had been originally randomlyassigned to ACEI therapy at inclusion in BENEDICT than in those who started ACEI therapy only afterconclusion of the trial. These findings extend previous and more robust data from HOPE–The OngoingOutcomes study showing that the protective effect of ACEI therapy against cardiovascular events observedduring the HOPE trial was sustained during 2.6 years extended follow-up, while all patients were receivingthe same ACEI therapy. These findings led the authors to suggest that the 4.5 years of initial “earlier” useof ramipril therapy during the HOPE trial provided greater cardioprotection compared with laterinitiation, possibly because of benefits on endothelial or vascular structure and function that persistedbeyond the blinded treatment period of the trial. Conceivably, the above considerations could apply alsoto our study population.The major limitation of this study is that this was an extension of a clinical trial originally designed forother purposes. Thus, study findings are hypothesis generating and need to be tested in ad hoc prospectivestudies. However, extension data could be recorded on the basis of preplanned monitoring guidelines inalmost 90% of patients completing BENEDICT, and exhaustive survival data could be obtained by theHealth Authorities Registry. Moreover, baseline characteristics of patients with or without extension datawere similar, as well as their original allocation to ACE or non-ACEI therapy. A major strength is thecentralized measurement of albuminuria—along with all other laboratory variables—by gold standardprocedures in triplicate overnight urine collections. Study findings may be widely generalizablebecause outcome data were observed in patients with type 2 diabetes with normoalbuminuria andhypertension, a type of patient representing at least 90% of the whole diabetic population. In addition, thefollow-up was the longest among similar studies thus far reported that considered the relationship betweenbaseline albuminuria and cardiovascular outcomes in patients with or without diabetes. Finally, consistencyof the results obtained by using fractional polynomial models or spline functions provided additional

16

7

17

18 19 209,21

22

13

1323

9,10,24


5 de 15 7/08/2015 2:52 a. m.

evidence of the robustness of the study findings. Another unique strength was that, unlike data fromprevious series in the general population or in patients with left ventricular hypertrophy or increasedcardiovascular risk that included also patients with micro- or macroalbuminuria (who most likely “drove”the study findings), our present data definitely confirmed the independent predictive value of albuminuriain a pure population of patients with type 2 diabetes and normoalbuminuria. Whether the above findingscan be generalized to nonwhite populations or to persons without diabetes is matter of investigation.In conclusion, in patients with type 2 diabetes and normoalbuminuria, any degree of measurable urinaryalbumin bears a significant risk for cardiovascular events. The association between albuminuria and risk iscontinuous, and there is no threshold level that distinguishes patients at risk from those who are protectedfrom cardiovascular disease. This incremental risk almost fully dissipates with early ACEI therapy. Futurerandomized trials are needed to identify levels of albuminuria above which cardioprotective therapy isappreciably beneficial in this population.Concise MethodsThe BENEDICT Extension StudyBENEDICT-A has been described elsewhere. In brief, from 1997 to 2000, a total of 1209 patientswith type 2 diabetes and hypertension, normoalbuminuria, creatinine <1.5 mg/dl, and HbA1c <11% wererandomly assigned to trandolapril, verapamil, their combination, or placebo in order to preventmicroalbuminuria. The current study was a preplanned extension study of BENEDICT-A that consisted ofclinical, laboratory, and case record evaluations until December 31, 2008. Finally, the Registry of theHealth District provided fatal events and causes of deaths. On the basis of BENEDICT results, after thetrial (January 2004), all patients received an ACEI. Overall, outcome data from BENEDICT with orwithout extension data were available for 1056 of the 1208 patients (87.4%) (Supplemental Figure 1).Definitions and MeasurementsBaseline normoalbuminuria was defined as UAE <20 µg/min for two of three overnight urine collections,and the median of the three measurements was used for analysis. Progression to microalbuminuria wasdiagnosed in patients with UAE ≥20 µg/min and <200 µg/min in two of three measurements.Cardiovascular OutcomesThe main outcome was the first onset of a component of a composite end point of fatal (including suddendeath) or nonfatal major cardiovascular events, such as coronary (acute myocardial infarction, unstableangina pectoris, or coronary revascularization by bypass grafting or percutaneous angioplasty),cerebrovascular (stroke, transient ischemic attack, pre–cerebral artery revascularization), or peripheralvascular (amputation, revascularization) disease and hospitalizations due to congestive heart failure. Allevents were defined a priori and were adjudicated under blind conditions by P.R. and E.P.Secondary outcomes were spontaneous components of the composite end point and coronary events.Statistical AnalysesThe relationships between baseline albuminuria and cardiovascular events were evaluated by Coxproportional hazards models. Confounders included baseline variables with a proven or possibleassociation with the outcome, such as age, sex, duration of diabetes, smoking, history of cardiovascularevents, body mass index, serum creatinine, HbA levels, randomization to ACEI therapy during the coretrial, mean arterial pressure, LDL-to-HDL cholesterol ratio, triglyceride and uric acid levels, and treatmentwith lipid-lowering therapy. Continuous variables, including albuminuria, were kept continuous.Colinearity was tested by Pearson correlation coefficient; when colinearity was found, only one variable

7,16 1514

9,10,24

1c


6 de 15 7/08/2015 2:52 a. m.

(HbA instead of glucose, LDL cholesterol instead of total cholesterol) or a surrogate (mean for systolic ordiastolic BP and the LDL-to-HDL ratio for both components of the ratio) was used. Variables with anonlinear association with risk (LDL-to-HDL ratio, albuminuria, and HbA and creatinine levels) werelog-transformed. The proportionality assumption was assessed using the log-rank and the weightedSchoenfeld residuals, and model goodness of fit was assessed by the Hosmer-Lemeshow test.Multivariable analysis was also performed by modeling baseline albuminuria with the fractionalpolynomial algorithm method (first and second degree), or a spline function, two flexible and informativeapproaches for the evaluation of possible nonlinear relationships between continuous variables andoutcomes. In preplanned sensitivity analyses, multivariable models were restricted to low-risk patients:those without previous cardiovascular events (n=1156) and those persistently normoalbuminuricthroughout BENEDICT (n=1107). Finally, analyses separately considered data from BENEDICT and theextension study and from patients originally randomly assigned to ACEI therapy or not. Data wereanalyzed using SPSS software, version 17.0.1, for Windows (SPSS, Inc., Chicago, IL) and Stata software,version 11.0 (fracpoly command; Stata Corp., Cary, NC).DisclosuresNone.Supplementary Material

Supplemental Data:

AcknowledgmentsThe authors are indebted to the staff of the Diabetology Units and of the Clinical Research Center for RareDiseases “Aldo & Cele Daccò” of the Mario Negri Institute for their assistance in the selection of and carefor the patients in this study; to Diletta Valsecchi for monitoring the data handling; and to Manuela Passerafor assistance with the preparation of the manuscript.Abbott (Ludwigshafen, Germany) sponsored BENEDICT. E.P. is the recipient of a long-term fellowshipfrom the European Renal Association–European Dialysis Transplant Association, which allowed him apostdoctoral position in the Mario Negri Institute.This study was an academic, internally funded study. No sponsor or company was involved in the datarecording; study design, analysis, interpretation, and reporting; manuscript preparation; or decision tosubmit the article for publication. For a complete list of study investigators, see the Supplemental Material.FootnotesPublished online ahead of print. Publication date available at www.jasn.org.See related editorial, “Urinary Albumin: How Low Is Normal?,” on pages 1605–1607.This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2012030252/-/DCSupplemental.References1. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR.; UKPDS GROUP: Developmentand progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study(UKPDS 64). Kidney Int 63: 225–232, 2003 [PubMed: 12472787]2. Dinneen SF, Gerstein HC.: The association of microalbuminuria and mortality in non-insulin-dependent

1c

1c

25,26


7 de 15 7/08/2015 2:52 a. m.

diabetes mellitus. A systematic overview of the literature. Arch Intern Med 157: 1413–1418, 1997[PubMed: 9224218]3. Nelson RG, Pettitt DJ, Carraher MJ, Baird HR, Knowler WC.: Effect of proteinuria on mortality inNIDDM. Diabetes 37: 1499–1504, 1988 [PubMed: 3181642]4. Rayner M, Petersen S, Buckley C., Press V: Coronary heart disease statistics: Diabetes supplement. 2001edition. Available at: http://www.bhf.org.uk/publications/view-publication.aspx?ps=1001401 Accessed onAugust 8, 20125. Mattock MB, Barnes DJ, Viberti G, Keen H, Burt D, Hughes JM, Fitzgerald AP, Sandhu B, Jackson PG.:Microalbuminuria and coronary heart disease in NIDDM: An incidence study. Diabetes 47: 1786–1792,1998 [PubMed: 9792549]6. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS.: Urinary albumin excretion.An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol 19: 1992–1997, 1999[PubMed: 10446083]7. Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, Gans RO, JanssenWM, Grobbee DE, de Jong PE.; Prevention of Renal and Vascular End Stage Disease (PREVEND) StudyGroup: Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in generalpopulation. Circulation 106: 1777–1782, 2002 [PubMed: 12356629]8. Ruggenenti P, Remuzzi G.: Time to abandon microalbuminuria? Kidney Int 70: 1214–1222, 2006[PubMed: 16871239]9. Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, GanevaM, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G.; BergamoNephrologic Diabetes Complications Trial (BENEDICT) Investigators: Preventing microalbuminuria intype 2 diabetes. N Engl J Med 351: 1941–1951, 2004 [PubMed: 15516697]10. Ruggenenti P, Perna A, Ganeva M, Ene-Iordache B, Remuzzi G.; BENEDICT Study Group: Impact ofblood pressure control and angiotensin-converting enzyme inhibitor therapy on new-onsetmicroalbuminuria in type 2 diabetes: A post hoc analysis of the BENEDICT trial. J Am Soc Nephrol 17:3472–3481, 2006 [PubMed: 17082240]11. De Cosmo S, Motterlini N, Prudente S, Pellegrini F, Trevisan R, Bossi A, Remuzzi G, Trischitta V,Ruggenenti P.; BENEDICT Study Group: Impact of the PPAR-gamma2 Pro12Ala polymorphism and ACEinhibitor therapy on new-onset microalbuminuria in type 2 diabetes: evidence from BENEDICT. Diabetes58: 2920–2929, 2009 [PMCID: PMC2780880] [PubMed: 19720797]12. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of DiabetesInterventions and Complications Research Group : Sustained effect of intensive treatment of type 1diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of DiabetesInterventions and Complications (EDIC) study. JAMA 290: 2159–2167, 2003 [PMCID: PMC2622725][PubMed: 14570951]13. Bosch J, Lonn E, Pogue J, Arnold JM, Dagenais GR, Yusuf S.; HOPE/HOPE-TOO Study Investigators:Long-term effects of ramipril on cardiovascular events and on diabetes: Results of the HOPE studyextension. Circulation 112: 1339–1346, 2005 [PubMed: 16129815]14. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Hallé JP, Young J, Rashkow A,Joyce C, Nawaz S, Yusuf S.; HOPE Study Investigators: Albuminuria and risk of cardiovascular events,death, and heart failure in diabetic and nondiabetic individuals. JAMA 286: 421–426, 2001


8 de 15 7/08/2015 2:52 a. m.

[PubMed: 11466120]15. Wachtell K, Ibsen H, Olsen MH, Borch-Johnsen K, Lindholm LH, Mogensen CE, Dahlöf B, DevereuxRB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristianson K, Lederballe-Pedersen O,Nieminen MS, Okin PM, Omvik P, Oparil S, Wedel H, Snapinn SM, Aurup P.: Albuminuria andcardiovascular risk in hypertensive patients with left ventricular hypertrophy: The LIFE study. Ann InternMed 139: 901–906, 2003 [PubMed: 14644892]16. Arnlöv J, Evans JC, Meigs JB, Wang TJ, Fox CS, Levy D, Benjamin EJ, D’Agostino RB, Vasan RS.:Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabeticindividuals: The Framingham Heart Study. Circulation 112: 969–975, 2005 [PubMed: 16087792]17. Forman JP, Brenner BM.: ‘Hypertension’ and ‘microalbuminuria’: The bell tolls for thee. Kidney Int69: 22–28, 2006 [PubMed: 16374419]18. Pistrosch F, Herbrig K, Kindel B, Passauer J, Fischer S, Gross P.: Rosiglitazone improves glomerularhyperfiltration, renal endothelial dysfunction, and microalbuminuria of incipient diabetic nephropathy inpatients. Diabetes 54: 2206–2211, 2005 [PubMed: 15983223]19. Chagnac A, Weinstein T, Herman M, Hirsh J, Gafter U, Ori Y.: The effects of weight loss on renalfunction in patients with severe obesity. J Am Soc Nephrol 14: 1480–1486, 2003 [PubMed: 12761248]20. UK Prospective Diabetes Study Group : Tight blood pressure control and risk of macrovascular andmicrovascular complications in type 2 diabetes: UKPDS 38. BMJ 317: 703–713, 1998[PMCID: PMC28659] [PubMed: 9732337]21. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P.; Irbesartan in Patientswith Type 2 Diabetes and Microalbuminuria Study Group: The effect of irbesartan on the development ofdiabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345: 870–878, 2001[PubMed: 11565519]22. Brouwers FP, Asselbergs FW, Hillege HL, de Boer RA, Gansevoort RT, van Veldhuisen DJ, van GilstWH.: Long-term effects of fosinopril and pravastatin on cardiovascular events in subjects withmicroalbuminuria: Ten years of follow-up of Prevention of Renal and Vascular End-stage DiseaseIntervention Trial (PREVEND IT). Am Heart J 161: 1171–1178, 2011 [PubMed: 21641365]23. Mancini GB, Henry GC, Macaya C, O’Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H,Lüscher TF, Klibaner MI, Haber HE, Uprichard AC, Pepine CJ, Pitt B.: Angiotensin-converting enzymeinhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary arterydisease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation 94: 258–265, 1996[PubMed: 8759064]24. BENEDICT Group : The BErgamo NEphrologic DIabetes Complications Trial (BENEDICT): Designand baseline characteristics. Control Clin Trials 24: 442–461, 2003 [PubMed: 12865039]25. Royston P, Altman DG, Sauerbrei W.: Dichotomizing continuous predictors in multiple regression: Abad idea. Stat Med 25: 127–141, 2006 [PubMed: 16217841]26. Royston P, Sauerbrei W.: Multivariable Model-Building. A Pragmatic Approach to Regression AnalysisBased on Fractional Polynomials for Modelling Continuous Variables, West Sussex, United Kingdom, JWiley, 2008.Figures and Tables


9 de 15 7/08/2015 2:52 a. m.

Table 1.Baseline characteristics of the overall study group and of patients with or without major cardiovascularevents during follow-upCharacteristic Overall Without Events With Events P ValuePatients, n (%) 1208 1019 (84.4) 189 (15.6)Age (yr) 62.33±8.05 61.85±8.12 64.92±7.15 <0.001Men, n (%) 638 (52.8) 521 (51.1) 117 (61.9) 0.004History of cardiovascular events 52 (4.3) 34 (3.3) 18 (9.5) <0.001Known duration of diabetes (yr) 6 (3–11) 6 (2–11) 7 (3–12) 0.18Smoking status, n (%) Never smoked 700 (57.9) 600 (58.9) 100 (52.9) 0.20 Former smoker 362 (30.0) 302 (29.6) 60 (31.7) Current smoker 146 (12.1) 117 (11.5) 29 (15.3)Body mass index (kg/m ) 29.08±4.72 29.16±4.72 28.66±4.68 0.19Trough BP (mmHg) Systolic 150.82±14.16 150.77±14.17 151.10±14.16 0.77 Diastolic 87.46±7.63 87.60±7.47 86.60±8.44 0.13 Mean 108.58±8.35 108.66±8.21 108.17±9.07 0.45Glycosylated hemoglobin (%) 5.79±1.37 5.73±1.36 6.16±1.37 <0.001Glucose (mg/dl) 161.34±47.05 160.00±46.67 168.52±48.57 0.03Cholesterol (mg/dl) Total 209.78±36.74 209.05±37.21 213.67±33.93 0.11 HDL 46.94±12.06 47.29±12.11 45.06±11.65 0.02 LDL 162.75±36.05 161.60±36.36 168.82±33.81 0.01Triglycerides 125 (91–181) 124 (91–177) 134 (91–194) 0.12Serum creatinine (mg/dl) 0.90±0.16 0.90±0.15 0.93±0.17 0.02Uric acid (mg/dl) 4.09±1.18 5.01±1.19 5.00±1.13 0.90Albuminuria (μg/min) 5.24 (3.5–9.3) 5.09 (3.5–8.7) 7.08 (3.7–11.6) <0.001Allocation to study treatments, n (%) Placebo 302 (25.0) 258 (25.3) 44 (23.3) 0.15 Verapamil 303 (25.1) 243 (23.8) 60 (31.7) Trandolapril 302 (25) 259 (25.4) 43 (22.8) Verapamil plus trandolapril 301 (24.9) 259 (25.4) 42 (22.2)Use of antihypertensive agents, n (%) 664 (55.0) 556 (54.6) 108(57.1) 0.32Number of antihypertensive agents 2 (1–2) 2 (1–2) 2 (1–3) 0.28Antilipidemic agents, n (%) 138 (11.4) 119 (11.7) 19 (10.0) 0.30Aspirin, n (%) 28 (2.3) 17 (1.7) 11 (5.8) 0.002Duration of follow-up (yr) 9.12 (6.16–9.86) 9.09 (6.0–9.81) 9.28 (7.7–10.10) 0.03

a

2

bc


10 de 15 7/08/2015 2:52 a. m.

Data are numbers, percent values, mean ± SD, or median (interquartile range).With versus without events.Different from the study treatments.Including the study treatments.

abc


11 de 15 7/08/2015 2:52 a. m.

Table 2.Patients with first-onset fatal or nonfatal major cardiovascular events (primary end point)Event Patients (n)Coronary heart disease (n=105) Unstable angina pectoris 14 Unstable angina pectoris + stenting/revascularization 40 Acute myocardial infarction 46 Acute myocardial infarction + stenting/revascularization 5Congestive heart failure 11Stroke or transient ischemic attack (n=39) Stroke 24 Transient ischemic attack 15Sudden death 3Peripheral vascular disease (n=31) Severe carotid obstruction 5 Severe carotid obstruction + stenting or angioplasty 8 Severe peripheral obstruction 8 Severe peripheral obstruction + stenting or bypass surgery 10 Total 189


12 de 15 7/08/2015 2:52 a. m.

Table 3.Univariate and multivariable Cox proportional hazards regression analysis of covariates versus the primaryend point (major cardiovascular events)

Covariates Univariate Analysis Multivariable AnalysisHR (95% CI) P Value OR (95% CI) P Value

Age 1.05 (1.03–1.07) <0.001 1.06 (1.04–1.08) <0.001Female versus male 1.46 (1.09–1.96) 0.01 1.58 (1.07–2.32) 0.02Duration of diabetes 1.02 (1.002–1.043) 0.03 0.99 (0.97–1.02) 0.88History of cardiovascular disease 3.02 (1.85–4.91) <0.001 2.97 (1.79–4.93) <0.001Smoker status 1.38 (0.93–2.04) 0.11 1.25 (0.81–1.92) 0.31Body mass index 0.96 (0.95–1.009) 0.16 0.99 (0.96–1.03) 0.65Mean BP 0.99 (0.97–1.008) 0.31 0.98 (0.96–1.00) 0.05HbA 2.87 (1.56–5.27) 0.001 3.17 (1.55–6.48) 0.002LDL-to-HDL cholesterol ratio 1.93 (1.26– 2.94) 0.002 2.03 (1.21–3.39) 0.007Triglycerides 1.001 (0.999–1.003) 0.07 1.00 (0.99–1.002) 0.90Serum creatinine 2.54 (1.10–5.85) 0.03 0.86 (0.31–2.42) 0.78UAE 1.055 (1.026–1.086) <0.001 1.05 (1.02–1.08) 0.002Uric acid 1.002 (0.891–1.127) 0.97 1.01 (0.88–1.16) 0.90Allocation to ACEI 0.818 (0.614–1.089) 0.17 0.84 (0.63–1.13) 0.25Use of lipid-lowering therapy 0.857 (0.533–1.377) 0.52 0.79 (0.48–1.29) 0.34

OR, odds ratio.Variables log-transformed.

1caa

aa

a


13 de 15 7/08/2015 2:52 a. m.

Figure 1.

Adjusted HRs for major cardiovascular events according to baseline albuminuria. Solid line shows estimated relation whenlogarithmic hazard is modeled as linear function of log (UAE). The reference value (HR = 1) is set at UAE = 1 μg/min.The shaded area includes the 95% CIs for more general functional relation, as estimated by P-splines. The HRs areadjusted for age, sex, duration of diabetes, history of cardiovascular events, smoking habit, body mass index, mean BP,logarithms of HbA , LDL-to-HDL cholesterol ratio, triglyceride and serum creatinine levels, and whether patient wasallocated to ACEI therapy. CVD, cardiovascular disease.

1c


14 de 15 7/08/2015 2:52 a. m.

Figure 2.

Adjusted HRs for major cardiovascular events according to baseline albuminuria in patients who during the BENEDICTtrial had been randomly allocated to ACEI therapy with trandolapril alone or combined to verapamil (solid line) or tonon-ACEI therapy with verapamil alone or placebo (dashed line). The lines show estimated relation when logarithmichazard is modeled as linear function of log (UAE). The reference value (HR = 1) is set at UAE = 1 μg/min. The HRs areadjusted for age, sex, duration of diabetes, history of cardiovascular events, smoking habit, body mass index, mean BP,logarithms of HbA , LDL-to-HDL cholesterol ratio, triglyceride and serum creatinine levels, and whether patient wasallocated to ACEI therapy. CVD, cardiovascular disease.

Articles from Journal of the American Society of Nephrology : JASN are provided here courtesy of AmericanSociety of Nephrology

1c


15 de 15 7/08/2015 2:52 a. m.

measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2...

Documents