Clinical Epidemiology

Measurable Urinary Albumin Predicts Cardiovascular Risk among Normoalbuminuric Patients with Type 2 Diabetes

Piero Ruggenenti, Esteban Porrini, Nicola Motterlini, Annalisa Perna, Aneliya Parvanova Ilieva, Ilian Petrov Iliev, Alessandro Roberto Dodesini, Roberto Trevisan, Antonio Bossi, Giuseppe Sampietro, Enrica Capitoni, Flavio Gaspari, Nadia Rubis, Bogdan Ene-Iordache, Giuseppe Remuzzi and for the BENEDICT Study Investigators
JASN October 2012, 23 (10) 1717-1724; DOI: https://doi.org/10.1681/ASN.2012030252

Abstract

Micro- or macroalbuminuria is associated with increased cardiovascular risk factors among patients with type 2 diabetes, but whether albuminuria within the normal range predicts long-term cardiovascular risk is unknown. We evaluated the relationships between albuminuria and cardiovascular events in 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BErgamo NEphrologic Diabetes Complication 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 to the first of fatal or nonfatal myocardial infarction; stroke; coronary, carotid, or peripheral artery revascularization; or hospitalization for heart failure. Overall, 189 (15.6%) of the patients experienced a main outcome event (2.14 events/100 patient-years); 24 events were fatal. Albuminuria independently predicted events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02–1.08). Second-degree polynomial multivariable analysis showed a continuous nonlinear relationship between albuminuria and events without thresholds. Considering the entire study population, even albuminuria at 1–2 μg/min was significantly 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-ACEI therapy. Among those originally receiving ACEI therapy, however, the event rate was uniformly low and was not significantly associated with albuminuria. Taken together, among normoalbuminuric patients with type 2 diabetes, any degree of measurable albuminuria bears significant cardiovascular risk. The association 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 2–12 times that observed in patients with less albuminuria.1,2 This largely accounts for the excess cardiovascular mortality observed in patients with diabetes compared with age-matched persons without the disease.1,3,4 Conversely, diabetic patients with UAE <20 μg/min (the upper limit of what is generally considered the normal range) are supposed to have a cardiovascular risk close to that of the general population.5–7 However, this cutoff was introduced a priori in clinical use and research based on the observation that 95% of “normal” individuals had excretion rates below that limit.8 Whether this value reflects a real threshold for cardiovascular risk or whether any measurable amount of albuminuria bears a significant risk, even within the normal range, is unknown, particularly in the diabetic population. Whether there is a level for albuminuria that differentiates patients who need cardioprotective intervention from those with a low risk who are unlikely to be affected by any treatment is also elusive. This is a major health issue because persons with normoalbuminuria account for the large majority of the diabetic population, and promptly identifying those at risk and providing them with preventive strategies before they progress to more 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)9 and eventually followed for approximately 10 years. In BENEDICT, at similar BP control, angiotensin-converting enzyme inhibitor (ACEI) treatment with trandolapril alone or in combination with the nondihydropyridine calcium-channel blocker verapamil halved the incidence of microalbuminuria compared with verapamil alone or placebo.9,10

We primarily sought to address whether and to what extent baseline albuminuria was associated with long-term incidence of fatal and nonfatal cardiovascular events in the above population. Secondarily, we explored whether earlier treatment with an ACEI translated into more effective cardioprotection in the long term and whether there was a threshold for baseline albuminuria above which this effect became apparent.

Results

Baseline Characteristics

Median UAE at inclusion was 5.24 (range, 0.44–19.85) μg/min. UAE exceeded 14 μg/min in only 10% of participants (Table 1). Baseline characteristics of study participants were similar to those of the 139 patients who did not enter the BENEDICT extension study, with the exception of a higher prevalence of men, lower hemoglobin A1c (HbA1c), and lower LDL-to-HDL cholesterol ratio in included participants (Supplemental Table 1). A similar proportion of patients originally randomly assigned in BENEDICT to trandolapril or non-ACEI therapy was receiving ACEI (87.5%) or statin (50.5%) therapy during the extension study.

View this table:
Table 1.

Baseline characteristics of the overall study group and of patients with or without major cardiovascular events during follow-up

Outcomes

During a median follow-up of 9.12 (interquartile range, 6.16–9.86) years, 168 patients died, 37 (22%) of cardiovascular causes. Overall, 212 major cardiovascular events were observed in 189 patients.

Primary Composite End-Point

Overall, first onset of a component of the composite end point of major cardiovascular 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).

View this table:
Table 2.

Patients with first-onset fatal or nonfatal major cardiovascular events (primary end point)

Throughout the whole observation period, there were 2.14 patients with the end point event every 100 patients per year. Overall, there were 55 end point events (4 fatal) during BENEDICT-A and 133 (20 fatal) during the extension study.

Compared with patients without cardiovascular events, those progressing to the end point were older and more frequently male, more frequently reported a cardiovascular event before study inclusion, and had more albuminuria and higher HbA1c and serum LDL-to-HDL cholesterol ratio (Table 1). Other baseline characteristics (including BP; concomitant antihypertensive, antidiabetic, and lipid-lowering treatment; and whether patient was allocated to ACEI therapy) were similar between groups with or without end point events.

Baseline Characteristics and Cardiovascular Risk

At univariable Cox proportional hazards regression analysis, older age; male sex; a longer duration of diabetes; previous cardiovascular events; and higher LDL-to-HDL cholesterol ratio, creatinine levels, and albuminuria levels were significantly associated with a higher risk for new-onset cardiovascular events (Table 3). At multivariable analysis, albuminuria was significantly associated with risk for cardiovascular events (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.02–1.08). On average, for 1 μg/min excess of albuminuria at baseline there was a 6% risk for progression to the end point on follow-up. Other independent predictors of events were older age, male sex, previous cardiovascular events, higher HbA1c levels, and higher LDL-to-HDL cholesterol ratio. No significant interaction between albuminuria and the other baseline covariates was observed. The assumption of proportionality was not violated (Schoenfeld residuals: P=0.26).

View this table:
Table 3.

Univariate and multivariable Cox proportional hazards regression analysis of covariates versus the primary end point (major cardiovascular events)

The second-degree polynomial transformation of albuminuria described the relationship with the cardiovascular 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-degree polynomial transformation in the multivariable analysis showed a continuous nonlinear relationship between albuminuria and cardiovascular events (Figure 1). A significant excess risk for progression to the end point was already evident for a UAE ranging from 1 to 2 µg/min compared with an excretion <1 µg/min (HR, 1.04; 95% CI, 1.02–1.07) taken as the reference value. The risk for events compared with the reference albuminuria level tended to plateau (HR, 2.49; 95% CI, 1.56–4.00) between albuminuria values of 13 and 14 µg/min (Figure 1 and Supplemental Table 2). Results were similar when baseline albuminuria was modeled with a spline function (data not shown). Cardiovascular risk at higher levels of albuminuria was not considered because of the too small number of patients and events.

Figure 1.
Figure 1.

Adjusted HRs for major cardiovascular events according to baseline albuminuria. Solid line shows estimated relation when logarithmic 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 are adjusted for age, sex, duration of diabetes, history of cardiovascular events, smoking habit, body mass index, mean BP, logarithms of HbA1c, LDL-to-HDL cholesterol ratio, triglyceride and serum creatinine levels, and whether patient was allocated to ACEI therapy. CVD, cardiovascular disease.

Sensitivity Analyses

Relationships between albuminuria and outcomes similar to those described in the whole study group were observed when the analyses were restricted to low-risk patients without a history of cardiovascular events at inclusion or with persistent normoalbuminuria throughout BENEDICT, as well as when cardiovascular events were considered independent of revascularizations and amputations or when only coronary events were analyzed (data not shown). Unlike BP, albuminuria at the end of BENEDICT—that is, at baseline of the extension study—predicted cardiovascular events on subsequent follow-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 compared with those with persistent high-range normoalbuminuria (i.e., albuminuria <1 SD or >1 SD of the mean at baseline or at BENEDICT last visit, respectively) had a three-fold lower incidence of cardiovascular events during the extension study (8% versus 24%; P=0.027).

Cardiovascular Risk According to ACEI Therapy

Baseline characteristics of patients who had been originally allocated to ACEI therapy with trandolapril alone or combined with verapamil in BENEDICT were similar to those of patients randomly assigned to non-ACEI therapy with verapamil alone or placebo.11 Eighty-four of the 603 patients (13.9%) originally randomly assigned to ACEI therapy had at least one major cardiovascular event compared with 105 of the 605 patients (17.4%) randomly assigned to non-ACEI therapy (P=0.08). During BENEDICT, 27 (4.5%) participants receiving ACEI therapy progressed to the end 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 non-ACEI therapy, and the incidence of events was significantly lower in those with ACEI (9.5% versus 12.7%; P=0.043).

As in the study group considered as a whole, a continuous significant incremental risk for cardiovascular events for each 1 µg/min increase in albuminuria at baseline was observed in patients originally randomly assigned to non-ACEI therapy considered separately. Again, in this group a significant increase was already evident 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) between albuminuria values of 13 and 14 µg/min (Figure 2 and Supplemental Table 2). Of note, however, in patients originally randomly assigned to ACEI therapy, the risk for major cardiovascular events was uniformly low at any considered level of albuminuria at baseline, and no significant association was observed between any increment in albuminuria and cardiovascular events during the whole study period (Figure 2 and Supplemental Table 2).

Figure 2.
Figure 2.

Adjusted HRs for major cardiovascular events according to baseline albuminuria in patients who during the BENEDICT trial had been randomly allocated to ACEI therapy with trandolapril alone or combined to verapamil (solid line) or to non-ACEI therapy with verapamil alone or placebo (dashed line). The lines show estimated relation when logarithmic hazard is modeled as linear function of log (UAE). The reference value (HR = 1) is set at UAE = 1 μg/min. The HRs are adjusted for age, sex, duration of diabetes, history of cardiovascular events, smoking habit, body mass index, mean BP, logarithms of HbA1c, LDL-to-HDL cholesterol ratio, triglyceride and serum creatinine levels, and whether patient was allocated to ACEI therapy. CVD, cardiovascular disease.

Discussion

In this longitudinal observational study of >1000 patients with type 2 diabetes and normoalbuminuria, we found a continuous relationship between UAE rate at inclusion and incidence of major cardiovascular events during approximately 10 years of follow-up. For each 1 μg/min excess in baseline albuminuria, there was a progressive incremental risk for cardiovascular events up to a UAE of 13–14 μg/min. Above this level, 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, was already evident at an excretion rate ranging from 1 to 2 μg/min. The incremental incidence of cardiovascular events observed for each 1 μg/min excess in baseline UAE was significant in the study group as a whole as well as in the subgroup of patients who had been originally randomly assigned in BENEDICT to non-ACEI therapy with verapamil alone or placebo. Of note, however, the association between albuminuria and events was not significant in patients who had been randomly assigned to ACEI therapy with trandolapril alone or in combination with verapamil. Actually, in this subgroup the risk for events was uniformly low, independent of the extent of albuminuria at baseline.

The above findings were not explained by differences in patient characteristics or concomitant treatments because 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 between treatment groups. Thus, the finding that patients originally randomly assigned to trandolapril during BENEDICT tended to have fewer cardiovascular events than those who received the same treatment only after inclusion in the extension study was consistent with the hypothesis that early ACEI therapy is more cardioprotective than late intervention. These data—which require confirmation in ad hoc prospective studies—extend previous evidence of sustained long-term benefit of early intensified metabolic control in an extension study of the Diabetes Control and Complications Trial12 and suggest that the same “memory” effect could apply also to ACEI, as already observed in the Heart Outcomes Prevention Evaluation (HOPE) study extension.13

A qualifying aspect of the present study was that for the first time evidence for a continuous relationship between albuminuria and risk was formally provided in patients with normoalbuminuria to start with. The HOPE study14 found that in patients at increased cardiovascular risk, the relationship between albuminuria and cardiovascular events extended to as low as 0.5 mg of urinary albumin for 1 mmol of urinary creatinine, while the Losartan Intervention For End-point reduction in hypertension (LIFE) study15 found a similar relationship between albuminuria and events among patients with left ventricular hypertrophy. The Framingham Heart Study showed that 6-year risk for cardiovascular disease was three-fold higher in nonhypertensive, nondiabetic persons with a urinary albumin-to-creatinine ratio above the sex-specific median (3.9 mg/min for men and 7.5 mg/min for women) than in those with a ratio below that level.16 Consistently, the Prevention of Renal and Vascular End Stage Disease (PREVEND) study found that independent of the effects of other cardiovascular risk factors, UAE was a predictor of cardiovascular mortality in the general population; the excess cardiovascular risk was already apparent at levels currently considered to be normal.7 All the preceding studies, however, included patients with a UAE ranging from very 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 macroalbuminuria and excess cardiovascular risk. Conversely, the present study allows us to conclude that, as for BP, the concept of a threshold level to define normality is inconsistent with available data17 and that any degree of measurable 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 by amelioration of insulin sensitivity,18 weight loss,19 BP, and blood glucose reduction20 and renin-angiotensin system inhibitor therapy.9,21 In the long run, these interventions are expected to prevent or delay end-organ damage.22 However, whether the above interventions are uniformly beneficial throughout the whole range of normoalbuminuria (or, rather, whether there is a threshold below which specific intervention is not associated with appreciable benefits) is unknown.

In this regard, it is noteworthy that in this study, the relationship between albuminuria and cardiovascular events was not appreciable in patients allocated to ACEI therapy during BENEDICT. Actually, in this treatment group baseline albuminuria was no longer predictive of cardiovascular events throughout the whole observation period. This was probably explained by a trend toward a progressively larger cardioprotective effect of trandolapril for progressively increasing levels of albuminuria. Independent of the above, during the extension study we observed fewer events in patients who had been originally randomly assigned to ACEI therapy at inclusion in BENEDICT than in those who started ACEI therapy only after conclusion of the trial. These findings extend previous and more robust data from HOPE–The Ongoing Outcomes study showing that the protective effect of ACEI therapy against cardiovascular events observed during the HOPE trial was sustained during 2.6 years extended follow-up, while all patients were receiving the same ACEI therapy.13 These findings led the authors to suggest that the 4.5 years of initial “earlier” use of ramipril therapy during the HOPE trial provided greater cardioprotection compared with later initiation,13 possibly because of benefits on endothelial or vascular structure and function that persisted beyond the blinded treatment period of the trial.23 Conceivably, the above considerations could apply also to our study population.

The major limitation of this study is that this was an extension of a clinical trial originally designed for other purposes. Thus, study findings are hypothesis generating and need to be tested in ad hoc prospective studies. However, extension data could be recorded on the basis of preplanned monitoring guidelines in almost 90% of patients completing BENEDICT, and exhaustive survival data could be obtained by the Health Authorities Registry. Moreover, baseline characteristics of patients with or without extension data were similar, as well as their original allocation to ACE or non-ACEI therapy. A major strength is the centralized measurement of albuminuria—along with all other laboratory variables—by gold standard procedures in triplicate overnight urine collections.9,10,24 Study findings may be widely generalizable because outcome data were observed in patients with type 2 diabetes with normoalbuminuria and hypertension, a type of patient representing at least 90% of the whole diabetic population. In addition, the follow-up was the longest among similar studies thus far reported that considered the relationship between baseline albuminuria and cardiovascular outcomes in patients with or without diabetes. Finally, consistency of the results obtained by using fractional polynomial models or spline functions provided additional evidence of the robustness of the study findings. Another unique strength was that, unlike data from previous series in the general population7,16 or in patients with left ventricular hypertrophy15 or increased cardiovascular risk14 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 albuminuria in a pure population of patients with type 2 diabetes and normoalbuminuria. Whether the above findings can 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 urinary albumin bears a significant risk for cardiovascular events. The association between albuminuria and risk is continuous, and there is no threshold level that distinguishes patients at risk from those who are protected from cardiovascular disease. This incremental risk almost fully dissipates with early ACEI therapy. Future randomized trials are needed to identify levels of albuminuria above which cardioprotective therapy is appreciably beneficial in this population.

Concise Methods

The BENEDICT Extension Study

BENEDICT-A has been described elsewhere.9,10,24 In brief, from 1997 to 2000, a total of 1209 patients with type 2 diabetes and hypertension, normoalbuminuria, creatinine <1.5 mg/dl, and HbA1c <11% were randomly assigned to trandolapril, verapamil, their combination, or placebo in order to prevent microalbuminuria. The current study was a preplanned extension study of BENEDICT-A that consisted of clinical, laboratory, and case record evaluations until December 31, 2008. Finally, the Registry of the Health District provided fatal events and causes of deaths. On the basis of BENEDICT results, after the trial (January 2004), all patients received an ACEI. Overall, outcome data from BENEDICT with or without extension data were available for 1056 of the 1208 patients (87.4%) (Supplemental Figure 1).

Definitions and Measurements

Baseline 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 was diagnosed in patients with UAE ≥20 µg/min and <200 µg/min in two of three measurements.

Cardiovascular Outcomes

The main outcome was the first onset of a component of a composite end point of fatal (including sudden death) or nonfatal major cardiovascular events, such as coronary (acute myocardial infarction, unstable angina pectoris, or coronary revascularization by bypass grafting or percutaneous angioplasty), cerebrovascular (stroke, transient ischemic attack, pre–cerebral artery revascularization), or peripheral vascular (amputation, revascularization) disease and hospitalizations due to congestive heart failure. All events 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 Analyses

The relationships between baseline albuminuria and cardiovascular events were evaluated by Cox proportional hazards models. Confounders included baseline variables with a proven or possible association with the outcome, such as age, sex, duration of diabetes, smoking, history of cardiovascular events, body mass index, serum creatinine, HbA1c levels, randomization to ACEI therapy during the core trial, mean arterial pressure, LDL-to-HDL cholesterol ratio, triglyceride and uric acid levels, and treatment with lipid-lowering therapy. Continuous variables, including albuminuria, were kept continuous. Colinearity was tested by Pearson correlation coefficient; when colinearity was found, only one variable (HbA1c instead of glucose, LDL cholesterol instead of total cholesterol) or a surrogate (mean for systolic or diastolic BP and the LDL-to-HDL ratio for both components of the ratio) was used. Variables with a nonlinear association with risk (LDL-to-HDL ratio, albuminuria, and HbA1c and creatinine levels) were log-transformed. The proportionality assumption was assessed using the log-rank and the weighted Schoenfeld residuals, and model goodness of fit was assessed by the Hosmer-Lemeshow test.

Multivariable analysis was also performed by modeling baseline albuminuria with the fractional polynomial algorithm method (first and second degree), or a spline function, two flexible and informative approaches for the evaluation of possible nonlinear relationships between continuous variables and outcomes.25,26 In preplanned sensitivity analyses, multivariable models were restricted to low-risk patients: those without previous cardiovascular events (n=1156) and those persistently normoalbuminuric throughout BENEDICT (n=1107). Finally, analyses separately considered data from BENEDICT and the extension study and from patients originally randomly assigned to ACEI therapy or not. Data were analyzed 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).

Disclosures

None.

Acknowledgments

The authors are indebted to the staff of the Diabetology Units and of the Clinical Research Center for Rare Diseases “Aldo & Cele Daccò” of the Mario Negri Institute for their assistance in the selection of and care for the patients in this study; to Diletta Valsecchi for monitoring the data handling; and to Manuela Passera for assistance with the preparation of the manuscript.

Abbott (Ludwigshafen, Germany) sponsored BENEDICT. E.P. is the recipient of a long-term fellowship from the European Renal Association–European Dialysis Transplant Association, which allowed him a postdoctoral position in the Mario Negri Institute.

This study was an academic, internally funded study. No sponsor or company was involved in the data recording; study design, analysis, interpretation, and reporting; manuscript preparation; or decision to submit the article for publication. For a complete list of study investigators, see the Supplemental Material.

Footnotes

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Measurable Urinary Albumin Predicts Cardiovascular Risk among Normoalbuminuric Patients with Type 2 Diabetes
Piero Ruggenenti, Esteban Porrini, Nicola Motterlini, Annalisa Perna, Aneliya Parvanova Ilieva, Ilian Petrov Iliev, Alessandro Roberto Dodesini, Roberto Trevisan, Antonio Bossi, Giuseppe Sampietro, Enrica Capitoni, Flavio Gaspari, Nadia Rubis, Bogdan Ene-Iordache, Giuseppe Remuzzi, for the BENEDICT Study Investigators
JASN Oct 2012, 23 (10) 1717-1724; DOI: 10.1681/ASN.2012030252
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