The incidence of cardiovascular disease (CVD)

Review Paper Pathogenesis and Treatment of Microalbuminuria in Patients With Diabetes: The Road Ahead Rigas Kalaitzidis, MD; George Bakris, MD The incidence of type 2 diabetes is increasing in the United States, which is expected to result in an increased prevalence of microalbuminuria and higher cardiovascular risk. Microalbuminuria is an indication that a low-level inflammatory process is ongoing. In patients with hypertension, with or without diabetes, increasing urinary albumin excretion (UAE) is associated with elevated levels of inflammatory markers, endothelial dysfunction, and platelet activation. Microalbuminuria is associated with an increased incidence of cardiovascular disease (CVD) morbidity and mortality in patients with hypertension and in those with diabetes with or without hypertension. Antihypertensive agents that modulate the renin-angiotensin-aldosterone system (RAAS) can delay the onset and reduce progression of microalbuminuria and decrease CVD morbidity and mortality in patients with diabetes. Clinical trials provide a spectrum of results regarding the protective effects of RAAS-blocking agents. Consideration of baseline blood pressure (BP), UAE and CVD risk, and the extent of BP lowering with treatment is necessary when interpreting clinical trial results in patients with From the Hypertensive Diseases Unit, Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL Address for correspondence: George Bakris, MD, Director, Hypertension Center, Endocrine Division (Diabetes Center), University of Chicago School of Medicine, 5841 South Maryland Avenue MC 1027, Chicago, IL 60637 E-mail: gbakris@gmail.com Manuscript received May 1, 2009; accepted July 21, 2009 doi: 10.1111/j.1751-7176.2009.00184.x microalbuminuria. It remains to be determined whether targeting the underlying inflammatory process can retard or prevent microalbuminuria progression or whether treatment of microalbuminuria can prevent end-stage renal disease or death. J Clin Hypertens (Greenwich). 2009;11:636 643. ª 2009 Wiley Periodicals, Inc. The incidence of cardiovascular disease (CVD) morbidity and mortality is declining in the United States. Contrary to this overall favorable trend, the proportion of patients with type 2 diabetes and CVD is increasing. The prevalence of chronic kidney disease (CKD) is also increasing, exacerbated in part by the increasing prevalence of type 2 diabetes. An increase in urinary albumin excretion (UAE) is a harbinger of CKD and other adverse outcomes in patients with diabetes. For this reason, it is recommended that UAE be closely monitored in patients with diabetes. A better understanding of factors that precipitate and or exacerbate microalbuminuria, and measures to prevent adverse outcomes associated with microalbuminuria, would be useful. EPIDEMIOLOGY AND CLINICAL SIGNIFICANCE The threshold UAE used to define microalbuminuria (ie, 30 300 lg albumin g creatinine in a spot urine collection) is traditionally considered to indicate an elevated risk of progression of CKD; however, the risk of CVD actually increases at lower thresholds, so the definition may need to be revised. The point prevalence of microalbuminuria in patients with type 2 diabetes varies widely (range, 6.5% 44%) depending on the population under study. 1 In the United States, the incidence of 636 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 11 NO. 11 NOVEMBER 2009

microalbuminuria is reported to be 1% to 2% per year, and the prevalence in patients with diabetes is estimated to be 43%. 2 This data fits well with the finding of the UK Prospective Diabetes Study (UKPDS) that about 50% of patients with type 2 diabetes develop microalbuminuria over their lifetime. 3 Among patients with microalbuminuria in the UKPDS, the rate of progression to macroalbuminuria was estimated to be 2.8% per year. 3 Albuminuria is associated with hypertension, salt sensitivity, hyperlipidemia, and diabetes. 4 Microalbuminuria is a subclinical indicator of ongoing target organ damage in patients with hypertension as well as in both hypertensive and nonhypertensive patients with diabetes. Hypertension and diabetes are the primary underlying causes of CKD, and among patients with diabetes, poor glycemic control is associated with an increased incidence of CKD, even in the absence of albuminuria at baseline. 5 However, the risk of CKD is higher in individuals with poor glycemic control and albuminuria. 5 EVIDENCE FOR MICROALBUMINURIA BEING AN INFLAMMATORY PHENOMENON Accumulating evidence suggests that microalbuminuria is a reflection of a more widespread inflammatory process throughout the vasculature. The acute phase reactant, high-sensitivity C-reactive protein (hscrp), is a marker of subclinical systemic inflammation that is perhaps the best studied marker of inflammation in patients with microalbuminuria. Serum hscrp levels are correlated with an increased risk of type 2 diabetes, hypertension, and CVD, and are elevated in patients with microalbuminuria. 6 8 In patients with newly diagnosed but as yet untreated hypertension, UAE and Cornell product (a measure of left ventricular hypertrophy [LVH]) were associated with elevated levels of inflammatory markers. 9 Serum hscrp levels and urinary excretion of tumor necrosis factor a (TNF-a) were elevated in patients with hypertension and microalbuminuria compared with normotensive controls in the study. When the analysis was restricted to patients with hypertension, with and without microalbuminuria, serum hscrp and urinary TNF-a levels were significantly higher in the former subgroup. 9 Other studies in newly diagnosed and untreated patients with hypertension have demonstrated a relationship between microalbuminuria and markers of endothelial activation including soluble E-selectin, 10 an endothelium-specific marker that is correlated with structural vascular damage, 11 Units 25 20 15 10 5 0 Normoalbuminuria (N=18) 2.0 a a 6.7 5.0 hscrp, mg/l 2.6 b 6.2 Serum TNF-α, pg/ml Microalbuminuria (N=29) b 13.0 3.2 2.0 Serum IL-6, pg/ml Macroalbuminuria (N=31) Urinary TNF-α, pg/mg Urinary IL-6, pg/mg and adhesion molecules (soluble intercellular cell adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]), 12 which participate in the initiating events of the atherosclerotic process. 13 In addition, patients with hypertension, microalbuminuria, and low-grade inflammation (as indicated by elevated hscrp serum levels) have enhanced platelet activation (as indicated by elevated levels of soluble CD40 ligand, soluble P-selectin, and von Willebrand factor). 14 Among patients with type 2 diabetes, inflammatory activation of peripheral blood mononuclear cells (PBMCs) and serum levels of inflammatory markers are correlated with UAE. 15 Serum and urinary levels of hscrp, TNF-a, interleukin 6 (IL-6), and UAE were elevated in patients with diabetes compared with nondiabetic controls. When patients were grouped according to UAE, serum levels of hscrp and TNF-a were significantly higher in patients with microalbuminuria or macroalbuminuria than in those with normoalbuminuria (Figure 1). Expression of mrna for TNF-a and IL-6 from PBMCs also increased in a graded manner, with the highest expression levels in patients with microalbuminuria and macroalbuminuria. 15 Increased levels of biomarkers of lowgrade inflammation (hscrp, IL-6, fibrinogen) and c,d 7.3 7.4 13.4 e 19.8 3.8 4.0 2.9 Figure 1. Mean levels of inflammatory markers in patients with type 2 diabetes with normoalbuminuria (mean urinary albumin excretion [UAE] 15.8 mg d), microalbuminuria (mean UAE 158 mg d), and macroalbuminuria (UAE 859 mg d). 15 Patients with normoalbuminuria were not receiving treatment with renin-angiotensin-aldosterone system (RAAS) blockers, but all patients with microalbuminuria or macroalbuminuria had received blockers of the RAAS for more than 76 months. All patients had a glomerular filtration rate >60 ml min. a P<.01 for microalbuminuria or macroalbuminuria vs normoalbuminuria; b P<.0001 for microalbuminuria or macroalbuminuria vs normoalbuminuria; c P<.0001 for macroalbuminuria vs normoalbuminuria; d P<.0001 for macroalbuminuria vs microalbuminuria; e P<.01 for macroalbuminuria vs microalbuminuria or normoalbuminuria. hscrp indicates high-sensitivity C-reactive protein; IL-6, interleukin 6; TNF-a, tumor necrosis factor a. VOL. 11 NO. 11 NOVEMBER 2009 THE JOURNAL OF CLINICAL HYPERTENSION 637

Patients, % 30 25 20 15 10 5 0 Composite Quintile 1 (<0.78) CV mortality Quintile 2 ( 0.78 to <1.94) All-cause mortality Quintile 3 ( 1.94 to <5.09) All-cause mortality Quintile 4 ( 5.09 to <16.9) Urinary albumin-creatinine ratio, mg/mmol Quintile 5 ( 16.9) Figure 2. Incidence of the composite end point, cardiovascular (CV) and all-cause mortality, stroke, and myocardial infarction (MI) in the subgroup of 1063 patients with diabetes, hypertension, and left ventricular hypertrophy in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. 18 Events are presented by quintiles of the urinary albumin:creatinine ratio at baseline. endothelial dysfunction (von Willebrand factor, VCAM-1, ICAM-1, soluble E-selectin), predicted development of nephropathy over 2 years of followup in patients with microalbuminuria and type 2 diabetes. 16 In contrast, serum levels of transforming growth factor-b and advanced glycation end products did not predict progression to nephropathy. 16 It is clear from the foregoing discussion that microalbuminuria is associated with an inflammatory process. This relationship may in fact be the common link that explains the well-established association between microalbuminuria and CVD. CVD IN PATIENTS WITH MICROALBUMINURIA Microalbuminuria is associated with an increased risk of adverse CVD outcomes in patients either with or without traditional risk factors for CVD. The risk of CVD morbidity and mortality increased in a continuous fashion in patients with hypertension and LVH enrolled in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) studyandinpatientswithstablecvdenrolledin the Heart Outcomes Prevention Evaluation (HOPE) and Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) studies, 17 with no apparent thresholds or plateaus. 18 The same trends were apparent in the subgroup of patients with diabetes enrolled in the LIFE (Figure 2) and HOPE studies. 18,19 The risk of a composite end point (CVD mortality, nonfatal myocardial infarction, nonfatal stroke) in patients with diabetes, hypertension, and LVH increased with increasing urinary albumin:creatinine MI ratio (UACR) in the LIFE study. 20 For the comparison between the lowest and highest quartiles of UACR, the adjusted hazard ratio for the composite end point increased by 2.1-fold. 20 TREATMENT FOR PATIENTS WITH MICROALBUMINURIA Lifestyle measures and drug therapies are used to slow the progression of renal disease in patients with diabetes. Tight control of BP and blood glucose can slow the progression of microvascular disease (including microalbuminuria). 1 Numerous studies have examined the impact of antihypertensive agents on the progression of CKD in patients with diabetes. Drugs that act on the renin-angiotensin-aldosterone system (RAAS) are effective antihypertensive agents that have been shown to slow progression of kidney disease, and their use is recommended in treatment guidelines for patients with diabetes at risk for CKD. 2,21 These and other agents have been evaluated in patients with microalbuminuria or at risk for microalbuminuria (Table I and Table II). The various clinical trials provide a wide spectrum of results as to the protective effects of RAAS agents relative to other drugs or placebo. In considering the results of the various clinical studies, it is important to consider where patients were on the continuum that encompasses normoalbuminuria through macroalbuminuria when the intervention was introduced (Figure 3). It is also necessary to consider baseline BP and CVD risk, as well as the details of the treatment regimens employed and the extent of BP lowering achieved with antihypertensive treatment. Given that microalbuminuria is now recognized to be associated with inflammation, it would be of interest to determine whether improvements in UAE are also associated with changes in inflammatory markers. It has been shown that some antihypertensive agents can decrease levels of inflammatory markersinpatientswith hypertension. 22 24 Importantly, the salutary effects of RAAS agents on UAE have been demonstrated to be independent of BP reduction. In the Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA)-2 trial, irbesartan reduced UAE in patients with type 2 diabetes, hypertension, and microalbuminuria. 25 After 2 years of treatment, significantly fewer patients randomized to irbesartan 300 mg d than placebo (5.2% vs 14.9%, respectively; P<.001) reached the primary end point in the trial (progression to macroalbuminuria). However, mean systolic BP (SBP) was significantly lower in recipients of irbesartan compared with placebo (Table II). 25 638 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 11 NO. 11 NOVEMBER 2009

Table I. Characteristics of Select Studies That Have Examined Antihypertensive Agents for Treatment of Patients With or At Risk for Microalbuminuria Study Patient Characteristics (No.) Primary End Point Treatment BENEDICT 33 r, db, mc, pc T2DM, HTN, normoalbuminuria (UAE <20 lg min) (1204) ABCD 35 r, db T2DM, normotension (480) Change in 24-h CrCl; UAE was a secondary end point IRMA-2 25 r, db, pc, mc UKPDS 39 r, mc microhope 27 r, db, pc ONTARGET (renal substudy) 29 r, db mc ADVANCE 30 r, db, mc, pc LIFE substudy 20 r, db, mc T2DM, MA (UAE 20 200 lg min), HTN (590) Baseline BP, mm Hg Baseline UAE or Other Measure of Renal Function Persistent MA (UAER 20 lg min) Trandolapril verapamil 151 87 5.3 lg min Trandolapril 151 87 5.0 lg min Verapamil 150 88 5.9 lg min Placebo 152 88 5.1 lg min T2DM, HTN (758) Fatal and nonfatal clinical end points related to diabetes; UAE was a secondary end point DM aged 55 y, with 1 CVD risk factor, without proteinuria (3577) Aged 55 y, with atherosclerosis or DM with TOD (25,620) T2DM aged 55 y with CVD risk factors (11,140) Intensive control (DBP 10 mm Hg below baseline) a 136 84 20 200 lg min: 21% of pts 200 lg min: 9% of pts Moderate control 137 84 20 200 lg min: 25% of pts (DBP of 80 89 mm Hg) a 200 lg min: 12% of pts UAER >200 lg min Irbesartan 150 mg d 153 90 58 lg min Irbesartan 300 mg d 153 91 53 lg min Placebo 153 90 55 lg min Combined end point (MI, stroke, or CV death); overt nephropathy was the main outcome in the substudy Composite of dialysis, doubling of SCr, and death Composite of macrovascular and microvascular events: death from CVD, nonfatal stroke, or MI, new or worsening renal or eye disease DM, HTN, LVH (1063) Composite of CVD death, MI, stroke across UACR quartile Captopril 25 50 mg BID 159 94 344 mg L Atenolol 50 100 mg d 159 93 297 mg L Ramipril 10 mg d 142 80 MA: 31% of pts Placebo 142 79 MA: 33% of pts Ramipril 10 mg d 142 82 20 200 lg min: 13% of pts Telmisartan 80 mg d 142 82 20 200 lg min: 13% of pts Ramipril telmisartan 142 82 20 200 lg min: 13% of pts Perindopril indapamide 137 78 20 200 lg min: 26% of pts UACR >300 lg mg: 4% of pts Placebo 137 78 20 200 lg min: 26% of pts UACR >300 lg mg: 4% of pts Losartan 176 97 UACR Q1 (1 mg mmol) UACR Q2 (1 3 mg mmol) UACR Q3 (3 12 mg mmol) UACR Q4 (12 mg mmol) Atenolol 177 97 UACR Q1 (1 mg mmol) UACR Q2 (1 3 mg mmol) UACR Q3 (3 12 mg mmol) UACR Q4 (12 mg mmol) Abbreviations: ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; BENEDICT, Bergamo Nephrologic Diabetes Complications Trial; BID, twice daily; CrCl, creatinine clearance; CVD, cardiovascular disease; db, double-blind; DBP, diastolic blood pressure (BP); DM, diabetes mellitus; HTN, hypertension; IRMA-2, Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria-2; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; LVH, left ventricular hypertrophy; MA, microalbuminuria; mc, multicenter; ONTARGET, Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial; pc, placebo-controlled; Q, quartile; r, randomized; SCr, serum creatinine; T2DM, type 2 DM; TOD, target organ damage; UACR, urinary albumin:creatinine ratio; UAE, urinary albumin excretion; UKPDS, UK Prospective Diabetes Study. a In the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, patients (pts) were randomized to intensive or moderate BP control and then randomized to enalapril or nisoldipine. VOL. 11 NO. 11 NOVEMBER 2009 THE JOURNAL OF CLINICAL HYPERTENSION 639

Table II. Outcomes in Select Studies That Have Examined Antihypertensive Agents for Treatment of Patients With or at Risk for Microalbuminuria Study (Duration of Follow-Up) Treatment BP, mm Hg Outcome BENEDICT 33 (median 3.6 y) ABCD 35 (5.3 y) IRMA-2 25 (2 y) UKPDS 39 (9 y) microhope 27 (4.5 y) ONTARGET (renal substudy) 29 (6 y) ADVANCE 30 (4.3 y) LIFE substudy 20 (4.8 y) Trandolapril verapamil 139 80 a P.002 vs PLA Pts with UAER 20 lg min: 5.7%; P=.01 vs PLA Trandolapril 139 81 a P.002 vs PLA Pts with UAER 20 lg min: 6.0%; P=.01 vs PLA Verapamil 141 82 a Pts with UAER 20 lg min: 11.9% Placebo 142 83 a Pts with UAER 20 lg min: 10% Intensive control 128 75 b D log UAE=0.36; P=.0001 vs moderate P<.0001 vs control moderate control No significant difference between pts treated with enalapril or nisoldipine Moderate control 137 81 b D log UAE=0.66 Irbesartan 150 mg d 143 83 a 19 pts developed nephropathy Irbesartan 300 mg d 141 83 a 10 pts developed nephropathy; P<.001 vs PLA Placebo 144 83 a 30 pts developed nephropathy Captopril 25 50 mg BID 144 83 a 5% of pts with UAER 300 mg L Atenolol 50 100 mg d 143 81 a 9% of pts with UAER 300 mg L P=.02 vs CAP for difference in DBP Ramipril 10 mg d DSBP DBP=)1.9 )3.3 CV death, MI, stroke: 15.3%; P=.0004 vs PLA P=.0002.008 vs PLA 7% of pts developed overt nephropathy; P=.27 vs PLA Placebo DSBP DBP=+0.6 )2.3 CV death, MI, stroke: 19.8% 8% of pts developed overt nephropathy Ramipril 10 mg d Not reported Dialysis, doubling of SCr, death: 13.5% of pts Telmisartan 80 mg d Not reported Dialysis, doubling of SCr, death: 13.4% of pts Ramipril telmisartan Not reported Dialysis, doubling of SCr, death: 14.5% of pts; P=.037 vs ramipril Perindopril indapamide DSBP DBP=)5.6 2.2 P<.0001 P<.0001 vs PLA Pts with a major macrovascular or microvascular event: 15.5%; P=.04 vs PLA Placebo Pts with a major macrovascular or microvascular event: 16.8% Losartan Not reported Composite end point in UACR Q1 (1 mg mmol): 11.4% Not reported Composite end point in UACR Q2 (1 3 mg mmol): 20.4% Composite end point in UACR Q3 (3 12 mg mmol): 20.4% Composite end point in UACR Q4 (12 mg mmol): 20.9%; P=.031 vs AT Atenolol Not reported Composite end point in UACR Q1 (1 mg mmol): 12.7% Composite end point in UACR Q2 (1 3 mg mmol): 19.5% Composite end point in UACR Q3 (3 12 mg mmol): 24.8% Composite end point in UACR Q4 (12 mg mmol): 31.8% Abbreviations: ABCD, Appropriate Blood Pressure Control in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; AML, amlodipine; AT, atenolol [Correction added after online publication 31-Aug-2009.]; BENEDICT, Bergamo Nephrologic Diabetes Complications Trial; BID, twice daily; BL, baseline; CAP, captopril; CV, cardiovascular; IRMA-2, Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria-2; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; ONTARGET, Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial; PLA, placebo; pts, patients; Q, quartile; SCr, serum creatinine; UACR, urinary albumin:creatinine ratio; UAE, urinary albumin excretion; UAER, UAE rate; UKPDS, UK Prospective Diabetes Study. a Mean systolic blood pressure (SBP) diastolic blood pressure (DBP) during the study. b SBP DBP at end of treatment. 640 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 11 NO. 11 NOVEMBER 2009

EFFECT ON CVD OUTCOMES In the HOPE study, treatment with ramipril significantly lowered the risk of a composite CVD event end point in patients 55 years and older with vascular disease or diabetes and at least 1 other cardiovascular risk factor (14.0% vs 17.8%; P<.001 vs placebo). 26 However, mean BP was consistently lower among ramipril recipients. 26 The benefit in the subgroup of patients with diabetes was consistent with the overall results, in whom the risk of progression to overt nephropathy was reduced by 24% in ramipril recipients (Table I and Table II). 27 A subsequent investigation, the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), compared the effects of ramipril with those of telmisartan in a patient population similar to that of HOPE. 28 The primary composite CVD outcome was documented in 16.5% and 16.7% of ramipril and telmisartan recipients, respectively, in whom BP reductions were similar. A third group of patients received ramipril plus telmisartan. Despite a greater reduction in BP in the latter group, the incidence of the primary end point was similar (16.3%) to that in the ramipril group, but the incidence of hyperkalemia (serum K + >5.5 mmol L) and discontinuation for hypotensive symptoms, syncope, diarrhea, and renal dysfunction was significantly higher. 28 Apreplanned subanalysis demonstrated the incidence of the combined renal outcome (dialysis, doubling of serum creatinine, and death) to be similar in recipients of either monotherapy and lower than in recipients of the combination (Table I and Table II). 29 In the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial, 30 treatment with a low-dose fixed combination of perindopril plus indapamide vs placebo produced a significant reduction in the incidence of a composite end point of macrovascular and microvascular events in patients 55 years and older with type 2 diabetes and at least 1 CVD risk factor. The reduction in the composite end point was largely due to a decrease in cardiovascular deaths (3.8% vs 4.6%; P=.27) and new-onset microalbuminuria (19.6% vs 23.5%; P<.001). Compared with patients with normoalbuminuria, the presence of either microalbuminuria or macroalbuminuria was independently associated with higher risks for cardiovascular death (3.0% vs 7.0%, respectively; hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.72 2.50), macrovascular events (7.4% vs 12.7%, respectively; HR, 1.61; 95% CI, 1.42 1.84), endstage kidney disease (0.2% vs 0.8%, respectively; HR, 1.99; 95% CI, 1.08 3.70), and all-cause death Normal ROADMAP Microalbuminuria IRMA 2 Proteinuria IDNT RENAAL Figure 3. The spectrum of urinary albumin excretion and intervention studies with angiotensin receptor blockers. IDNT indicates Irbesartan in Diabetic Nephropathy Trial 36 ; IRMA 2, Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria-2 25 ; RENAAL, Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan 37 ; ROADMAP, Randomised Olmesartan and Diabetes Microalbuminuria Prevention. 3 (6.3% vs 11.7%, respectively; HR, 1.70; 95% CI, 1.48 1.96) (all P<.03). 31 The mean SBP diastolic (DBP) was 145 81 mm Hg at baseline and more than 40% of patients had an SBP DBP <140 90 mm Hg at baseline. The intervention produced a significant meanreductioninbprelative to placebo (Table II). 30 The study confirms that early intervention with a RAAS agent and a diuretic can reduce the progression of macrovascular and microvascular events and reinforces the adage lower is better with respect to BP control in this high-risk population. 32 Secondary outcomes data from the previously mentioned IRMA-2 trial also lend support to the potential benefits of RAAS blockade in reducing cardiovascular events. Results from IRMA-2 showed a nonsignificant trend toward cardiovascular protection in the high-dose (ie, 300 mg d) irbesartan group in which nonfatal cardiovascular events were more frequent in the placebo group vs the irbesartan group (8.7% vs 4.5%, respectively; P=.11). An analysis of the LIFE study restricted to patients with diabetes and microalbuminuria at baseline showed that losartan produced greater reductions in albuminuria than atenolol during a mean of 4.7 years of treatment despite similar BP-lowering effects in both arms of the study. 20 The authors of the analysis estimated that approximately one fifth of the greater efficacy of losartan over atenolol in reducing CVD end points could be attributed to the greater reduction in UACR with losartan. 20 CAN MICROALBUMINURIA BE PREVENTED? Few studies have examined whether microalbuminuria can actually be prevented through the use of appropriate drug intervention. The prospective VOL. 11 NO. 11 NOVEMBER 2009 THE JOURNAL OF CLINICAL HYPERTENSION 641

Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) showed that treatment with an ACE inhibitor, alone or in combination with a calcium channel blocker (CCB), significantly decreased the incidence of microalbuminuria compared with either a CCB or placebo in normoalbuminuric patients with type 2 diabetes and hypertension (Table I and Table II). 33 The target SBP DBPinthe trial was 120 80 mm Hg and SBP DBP was significantly lower in recipients of trandolapril or trandolapril verapamil compared with placebo, but not verapamil alone. In contrast, the Appropriate Blood Pressure Control in Diabetes (ABCD) trial 34 suggested that there was no difference between the impact of an ACE inhibitor or CCB on the progression of albuminuria in normotensive patients with type 2 diabetes. 35 Patients in this trial were randomized to tight (DBP <75 mm Hg) or moderate BP control (DBP of 80 89 mm Hg). The mean SBP DBP during the last 4 years of the 5-year study was 128 75 mm Hg in the intensive group and 137 81 mm Hg in the moderate group. The change in log UAE was significantly lower in patients randomized to the intensive BP control group, although there was no difference between those treated with enalapril or nisoldipine. Significantly more patients in the intensive group reverted from microalbuminuria to normoalbuminuria in the tight control group, but no patient reverted from overt albuminuria to microalbuminuria during the study. 35 In contrast to previous studies such as IRMA 2, 25 which used pharmacologic intervention in patients already having microalbuminuria, or studies such as either the Irbesartan in Diabetic Nephropathy Trial (IDNT) 36 or the Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan (RENAAL) 37 trial wherein the patient populations had already developed proteinuria, an ongoing clinical trial, the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, should provide important answers as to whether RAAS-blocking agents can be used to interrupt the progression from normoalbuminuria to proteinuria. The ROADMAP study is the first large-scale, primary prevention study to determine whether treatment with an angiotensin receptor blocker (ARB) (olmesartan medoxomil) can prevent the onset of microalbuminuria in patients with diabetes and who have at least 1 additional cardiovascular risk factor. 38 Patients (N=4400) eligible for this randomized, double-blind, placebo-controlled, parallelgroup, multicenter, phase III study are required to have type 2 diabetes and normoalbuminuria (35 mg albumin g urine creatinine in women and 25 mg albumin g urine creatinine in men), as well as at least 1 cardiovascular risk factor. The primary efficacy end point is the time to occurrence of microalbuminuria. Secondary efficacy end points include the effects of treatment on CVD and renal morbidity and mortality. Patients are scheduled to receive olmesartan medoxomil 40 mg or placebo once daily, with the median duration of treatment expected to be up to 5 years. Recruitment of patients commenced in 2004. In addition to answering the question of whether an ARB can prevent or delay the onset of microalbuminuria, the ROADMAP study might also determine whether the prevention of microalbuminuria will translate into protection against, or reductions in, renal disease and or cardiovascular events. CONCLUSIONS The prevalence of microalbuminuria and diabetic kidney disease is expected to increase in the future. Microalbuminuria is an indicator of a widespread low-level inflammatory process and is associated with an increased incidence of CVD morbidity and mortality. There is evidence that treatment with antihypertensive agents that modulate the RAAS can delay the onset and reduce progression of microalbuminuria and decrease CVD morbidity and mortality in patients with diabetes. It remains to be determined whether treatment that targets the underlying inflammatory process can retard or prevent progression to microalbuminuria and, therefore, ultimately, CVD and renal morbidity and mortality. Acknowledgements and disclosures: The authors thank Blair Jarvis, MSc, and Alan J. Klopp, PhD, for providing editorial assistance in the preparation of this review. The preparation of this article was supported by Daiichi Sankyo, Inc. George Bakris, MD, serves as a consultant for Daiichi Sankyo, Inc. REFERENCES 1 Bakris GL. Microalbuminuria: Marker of Kidney and Cardiovascular Disease. London, UK: Current Medicine Group Ltd.; 2007. 2 KDOQI. Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007;49(suppl 2):S12 S154. 3 Adler AI, Stevens RJ, Manley SE, et al. Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63:225 232. 4 Danziger J. Importance of low-grade albuminuria. Mayo Clin Proc. 2008;83:806 812. 5 Bash LD, Selvin E, Steffes M, et al. Poor glycemic control in diabetes and the risk of incident chronic kidney disease even in the absence of albuminuria and retinopathy: Atherosclerosis Risk in Communities (ARIC) Study. Arch Intern Med. 2008;168:2440 2447. 642 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 11 NO. 11 NOVEMBER 2009

6 Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327 334. 7 Stuveling EM, Bakker SJL, Hillege HL, et al. C-reactive protein modifies the relationship between blood pressure and microalbuminuria. Hypertension. 2004;43:791 796. 8 Zethelius B, Berglund L, Sundstrom J, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med. 2008;358:2107 2116. 9 Navarro-Gonzalez JF, Mora C, Muros M, et al. Association of tumor necrosis factor-alpha with early target organ damage in newly diagnosed patients with essential hypertension. J Hypertens. 2008;26:2168 2175. 10 Tatasciore A, Zimarino M, Renda G, et al. Awake blood pressure variability, inflammatory markers and target organ damage in newly diagnosed hypertension. Hypertens Res. 2008;31:2137 2146. 11 De Caterina R, Ghiadoni L, Taddei S, et al. Soluble E-selectin in essential hypertension: a correlate of vascular structural changes. Am J Hypertens. 2001;14:259 266. 12 Cottone S, Mule G, Nardi E, et al. Microalbuminuria and early endothelial activation in essential hypertension. J Hum Hypertens. 2007;21:167 172. 13 Smith SJ. The role of integrin-mediated cell adhesion in health and disease: integrin-based therapy in clinical medicine. Ann Intern Med. 2000;132:333 336. 14 Ferroni P, Guagnano MT, Falco A, et al. Association of low-grade inflammation and platelet activation in patients with hypertension with microalbuminuria. Clin Sci (Lond). 2008;114:449 455. 15 Navarro JF, Mora C, Gomez M, et al. Influence of renal involvement on peripheral blood mononuclear cell expression behaviour of tumour necrosis factor-alpha and interleukin-6 in type 2 diabetic patients. Nephrol Dial Transplant. 2008;23:919 926. 16 Persson F, Rossing P, Hovind P, et al. Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study. Scand J Clin Lab Invest. 2008;68:731 738. 17 Solomon SD, Lin J, Solomon CG, et al. Influence of albuminuria on cardiovascular risk in patients with stable coronary artery disease. Circulation. 2007;116:2687 2693. 18 Wachtell K, Olsen MH, Dahlof B, et al. Microalbuminuria in hypertensive patients with electrocardiographic left ventricular hypertrophy: The LIFE study. J Hypertens. 2002;20:405 412. 19 Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286:421 426. 20 Ibsen H, Olsen MH, Wachtell K, et al. 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. 2006;29:595 600. 21 American Diabetes Association. Standards of medical care in diabetes 2006. Diabetes Care. 2006;29(suppl 1):S4 S42. 22 Fliser D, Buchholz K, Haller H. Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation. 2004; 110:1103 1107. 23 Palmas W, Ma S, Psaty B, et al. Antihypertensive medications and C-reactive protein in the multi-ethnic study of atherosclerosis. Am J Hypertens. 2007;20:233 241. 24 Yano Y, Hoshide S, Ishikawa J, et al. The differential effects of angiotensin II type 1 receptor blockers on microalbuminuria in relation to low-grade inflammation in metabolic hypertensive patients. Am J Hypertens. 2007; 20:565 572. 25 Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870 878. 26 Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145 153. 27 Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355:253 259. 28 Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547 1559. 29 Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008; 372:547 553. 30 Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829 840. 31 de Galan BE, Perkovic V, Ninomiya T, et al. Lowering blood pressure reduces renal events in type 2 diabetes. J Am Soc Nephrol. 2009;20:883 892. 32 Bakris GL, Berkwits M. Trials that matter: the effect of a fixed-dose combination of an Angiotensin-converting enzyme inhibitor and a diuretic on the complications of type 2 diabetes. Ann Intern Med. 2008;148:400 401. 33 Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med. 2004; 351:1941 1951. 34 Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645 652. 35 Schrier RW, Estacio RO, Esler A, et al. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002;61:1086 1097. 36 Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851 860. 37 Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861 869. 38 Haller H, Viberti GC, Mimran A, et al. Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study. J Hypertens. 2006;24:403 408. 39 United Kingdom Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998;317:713 720. VOL. 11 NO. 11 NOVEMBER 2009 THE JOURNAL OF CLINICAL HYPERTENSION 643